Metabolic homeostasis is maintained by redundant pathways to ensure adequate nutrient supply during fasting and other stresses. These pathways are regulated locally in tissues and systemically via the liver, kidney, and circulation. Here, we characterize how serine, glycine, and one-carbon (SGOC) metabolism fluxes across the eye, liver, and kidney sustain retinal amino acid levels and function. Individuals with macular telangiectasia (MacTel), an age-related retinal disease with reduced circulating serine and glycine, carrying deleterious alleles in SGOC metabolic enzymes exhibit an exaggerated reduction in circulating serine. A Phgdh+/- mouse model of this haploinsufficiency experiences accelerated retinal defects upon dietary serine/glycine restriction, highlighting how otherwise silent haploinsufficiencies can impact retinal health. We demonstrate that serine-associated retinopathy and peripheral neuropathy are reversible, as both are restored in mice upon serine supplementation. These data provide molecular insights into the genetic and metabolic drivers of neuro-retinal dysfunction while highlighting therapeutic opportunities to ameliorate this pathogenesis.

The resuscitation of polytrauma with hemorrhagic shock and traumatic brain injury (TBI) is a balance between permissive hypotension and maintaining vital organ perfusion. There is no current optimal solution. This study tested whether a multifunctional resuscitation cocktail supporting hemostasis and perfusion could mitigate blood loss while improving vital organ blood flow during prolonged limited resuscitation. Anesthetized Yorkshire swine were subjected to fluid percussion TBI, femur fracture, catheter hemorrhage, and aortic tear. Fluid resuscitation was started when lactate concentration reached 3–4 mmol/L. Animals were randomized to one of five groups. All groups received hydroxyethyl starch solution and vasopressin. Low- and high-dose fibrinogen (FBG) groups additionally received 100 and 200 mg/kg FBG, respectively. A third group received TXA and low-dose FBG. Two control groups received albumin, with one also including TXA. Animals were monitored for up to 6 h. Blood loss was decreased and vital organ blood flow was improved with low- and high-dose fibrinogen compared to albumin controls, but survival was not improved. There was no additional benefit of high- vs. low-dose FBG on blood loss or survival. TXA alone decreased blood loss but had no effect on survival, and combining TXA with FBG provided no additional benefit. Pooled analysis of all groups containing fibrinogen vs. albumin controls found improved survival, decreased blood loss, and improved vital organ blood flow with fibrinogen delivery. In conclusion, a low-volume resuscitation cocktail consisting of hydroxyethyl starch, vasopressin, and fibrinogen concentrate improved outcomes compare to controls during limited resuscitation of polytrauma.

Background. Coagulopathic bleeding is a major cause of mortality after trauma, and platelet dysfunction contributes to this problem. The causes of platelet dysfunction are unknown, but a great deal can be learned from the plasma environment after injury, which may directly alter platelet function. Studying the changes in plasma using untargeted proteomics would provide unbiased insight into the presence of possible inhibitors of platelet function, changes to their major ligands, or other previously unknown pathways affecting platelet function. Methods. Citrated blood was collected from severely injured trauma patients at the time of their arrival to the Emergency Department. Platelet testing was performed immediately, and plasma was frozen for analysis. Samples were collected from 110 patients, and a subset of 24 patients was identified by a preserved (n=12) or severely impaired (n=12) platelet aggregation response to five different agonists (adenosine diphosphate, arachidonic acid, collagen, thrombin receptor-activating peptide, and ristocetin). Untargeted proteomics was performed by nanoflow liquid chromatography tandem mass spectrometry to determine the plasma protein profile associated with platelet dysfunction. Protein abundance levels for each patient were normalized to total protein concentration to control for hemodilution by crystalloid fluid infusion prior to blood draw. Results were compared by Wilcoxon rank-sum test, and a two-tailed p value less than 0.05 was considered significant. No adjustment was made for multiple comparisons, as the risk of a type II error was felt to outweigh that of a type I error in this exploratory analysis. Results. Patients with platelet dysfunction were more severely injured (median Injury Severity Score 29.5 vs. 13.5, p=0.002) but otherwise demographically similar to those with retained platelet function. Of 232 proteins identified, twelve were significantly different in the low- vs. high-platelet function groups: gelsolin (median peak intensity 9.70E+6 vs. 1.48 E+7, p=0.002), transketolase (2.86E+4 vs. 9.36E+3, p=0.003), protein S100-A8 (4.60E+4 vs. 2.64E+4, p=0.006) and -A9 (5.83E+4 vs. 4.07E+4, p=0.012), histone H4 (5.72E+4 vs. 8.47E+6, p=0.007), histidine-rich glycoprotein (HRG) (5.00E+6 vs. 8.30E+6, p=0.008), factor XIII B chain (1.09E+6 vs. 1.61E+6, p=0.020), apolipoprotein A-IV (2.30E+7 vs. 3.28E+7, p=0.024), alpha-enolase (1.02E+5 vs. 4.15E+4, p=0.024), heat shock protein 90-alpha (1.41E+4 vs. 4.08E+3, p=0.045), alpha-2-HS-glycoprotein (2.83E+7 vs. 3.68E+7, p=0.045), and neutrophil gelatinase-associated lipocalin (3.44E+4 vs. 1.36E+4, p=0.045). These results are summarized in the figure, which shows one group of proteins that decreased in abundance (on the left side of the volcano plot) and another that increased (on the right side) in the patients with low platelet function. The twelve proteins that changed the most fall into several categories related to platelet function. Low gelsolin and high histone levels are each associated with microvascular obstruction by release of intracellular material that accumulates in small vessels and activates platelets. Low HRG and high damage-associated molecular pattern (DAMP) protein levels are consistent with massive innate immune activation, which can impair platelet function in many ways. Conclusion. This study provides an unbiased description of the change in proteomic profile associated with platelet dysfunction after trauma and identifies twelve proteins with the most profound changes. The pathways involving these proteins are salient targets for immediate investigation to better understand platelet dysfunction after trauma and identify targets for intervention. Figure Legend. Volcano plot depicting fold-change and statistical significance of individual proteins in patients with low vs. high platelet function. Dotted horizontal line represents p = 0.05. Twelve proteins showed a statistically significant p value. Figure Disclosures No relevant conflicts of interest to declare.

The decline in mitochondrial function has been associated and correlated with aging and various neurogenerative diseases. The mitochondria lie at a critical junction of several metabolic pathways, and metabolic reactions are highly compartmentalized across distinct tissues. As such, progressive mitochondrial defects will have diverse metabolic and phenotypic consequences that could reflect physiological changes that occur with aging. Here, we comprehensively characterized metabolic alterations in PolgD257A mitochondrial DNA mutator mice throughout the aging process. Plasma alanine increased dramatically with progressive loss of mitochondria, with lactate and other organic acids accumulating to a lesser extent. These changes are reflective of an increased glycolytic flux and rapid glucose turnover, and a reduced ability to oxidize keto acids, as demonstrated by [13C]glucose tracing. Amino acid changes were also suggestive of dysfunctional nitrogen metabolism, which was confirmed by quantifying [15N]ammonium incorporation into urea and amino acids. Additionally, progressive mitochondrial dysfunction led to alterations in the lipidome including sphingolipids. We observed the accumulation of 1‐deoxysphingolipids, which are synthesized by serine palmitoyltransferase (SPT) using alanine. Consistent with this metabolic rewiring, PolgD257A mice exhibit accelerated thermal hypoalgesia. These results highlight the distinct changes that occur in carbon and nitrogen metabolism upon mitochondrial loss and highlight key metabolic mechanisms which can drive aging associated neuropathy.

The oxidative pentose phosphate pathway (oxiPPP) contributes to cell metabolism through not only the production of metabolic intermediates and reductive NADPH but also inhibition of LKB1-AMPK signaling by ribulose-5-phosphate (Ru-5-P), the product of the third oxiPPP enzyme 6-phosphogluconate dehydrogenase (6PGD). However, we found that knockdown of glucose-6-phosphate dehydrogenase (G6PD), the first oxiPPP enzyme, did not affect AMPK activation despite decreased Ru-5-P and subsequent LKB1 activation, due to enhanced activity of PP2A, the upstream phosphatase of AMPK. In contrast, knockdown of 6PGD or 6-phosphogluconolactonase (PGLS), the second oxiPPP enzyme, reduced PP2A activity. Mechanistically, knockdown of G6PD or PGLS decreased or increased 6-phosphogluconolactone level, respectively, which enhanced the inhibitory phosphorylation of PP2A by Src. Furthermore, γ-6-phosphogluconolactone, an oxiPPP byproduct with unknown function generated through intramolecular rearrangement of δ-6-phosphogluconolactone, the only substrate of PGLS, bound to Src and enhanced PP2A recruitment. Together, oxiPPP regulates AMPK homeostasis by balancing the opposing LKB1 and PP2A.

Platelets contract forcefully after their activation, contributing to the strength and stability of platelet aggregates and fibrin clots during blood coagulation. Viscoelastic approaches can be used to assess platelet-induced clot strengthening, but they require thrombin and fibrin generation and are unable to measure platelet forces directly. Here, we report a rapid, microfluidic approach for measuring the contractile force of platelet aggregates for the detection of platelet dysfunction. We find that platelet forces are significantly reduced when blood samples are treated with inhibitors of myosin, GPIb-IX-V, integrin α IIb β 3, P2Y 12 , or thromboxane generation. Clinically, we find that platelet forces are measurably lower in cardiology patients taking aspirin. We also find that measuring platelet forces can identify Emergency Department trauma patients who subsequently require blood transfusions. Together, these findings indicate that microfluidic quantification of platelet forces may be a rapid and useful approach for monitoring both antiplatelet therapy and traumatic bleeding risk.

Alzheimer's disease (AD) is a growing global healthcare burden affecting the aging population and society. Given the lack of effective treatment to AD, early detection at the prodromal stage and timely monitoring of changes during progression are considered the best approach to control and intervene in disease progression. "Liquid biopsy" of AD biomarkers amyloid-β peptides (Aβs) and tau proteins in the cerebrospinal fluid (CSF) or blood samples holds great promises for cost-effective, widely accessible, and easy-administrated noninvasive detection and follow-up of AD. However, current in vitro detection methods have not yet demonstrated sufficient sensitivity and specificity using neither Aβs nor tau proteins biomarkers. One major challenge of accurate detection and measurement of biomarker levels in biofluidic samples is the biofouling effect with nonspecific adsorption of unwanted biomolecules, such as various serum proteins, on the surface of targeted detecting agents or devices, causing false-positive and false-negative findings. In this study, antibiofouling polymer polyethylene glycol-block-allyl glycidyl ether (PEG-b-AGE) coated magnetic iron oxide nanoparticles (IONPs) capable of suppressing the nonspecific interactions with biomolecules, especially proteins, were investigated for the immunomagnetic capturing of Aβ40 and Aβ42 peptides and tau protein spiked in CSF- and serum-mimicking samples using corresponding antibodies conjugated as targeting ligands. Antibody-conjugated antibiofouling IONPs demonstrated improved specificity (>90%) and sensitivity (>95%) over those of antibody-conjugated magnetic micron beads (Dynabeads, ∼50% specificity and 30-40% sensitivity) widely used as magnetic separating agents under the same experimental conditions with the presence of nontargeted interfering proteins. The antibody-conjugated IONPs also exhibited significantly higher sensitivities (80-90%) and better performance of capturing Aβs and tau protein from the human whole blood samples than antibody-conjugated Dynabeads (∼20%).

Introduction: Traumatic brain injury (TBI) and hemorrhagic shock (HS) are the leading causes of traumatic death worldwide and particularly on the battlefield. They are especially challenging when present simultaneously (polytrauma), and clear blood pressure end points during fluid resuscitation are not well described for this situation. The goal of this study is to evaluate for any benefit of increasing blood pressure using a vasopressor on brain blood flow during initial fluid resuscitation in a swine polytrauma model. Materials and Methods: We used a swine polytrauma model with simultaneous TBI, femur fracture, and HS with uncontrolled noncompressible internal bleeding from an aortic tear injury. Five animals were assigned to each of three experimental groups (hydroxyethyl starch only [HES], HES + 0.4 U/kg vasopressin, and no fluid resuscitation [No Fluids]). Fluids were given as two 10 mL/kg boluses according to tactical field care guidelines. Primary outcomes were mean arterial blood pressure (MAP) and brain blood flow at 60 min. Secondary outcomes were blood flows in the heart, intestine, and kidney; arterial blood lactate level; and survival at 6 hr. Organ blood flow was measured using injection of colored microspheres. Results: Five animals were tested in each of the three groups. There was a statistically significant increase in MAP with vasopressin compared with other experimental groups, but no significant increase in brain blood flow during the first 60 min of resuscitation. The vasopressin group also exhibited greater total internal hemorrhage volume and rate. There was no difference in survival at 6 hours. Conclusion: In this experimental swine polytrauma model, increasing blood pressure with vasopressin did not improve brain perfusion, likely due to increased internal hemorrhage. Effective hemostasis should remain the top priority for field treatment of the polytrauma casualty with TBI.

There is significant variability in blood coagulation among world populations. In particular, there may exist important differences in regulation of the fibrinolytic system in Asian populations that contribute to diseases of thrombosis and hemostasis. To investigate this issue, we compared fibrinogen concentration, plasma clot formation, and fibrinolytic resistance of healthy Asian subjects from Hat Yai, Songkhla, Thailand (Thai) vs. healthy North American subjects from Seattle, Washington, USA (SEA). Citrated plasma samples were obtained from healthy adult volunteers. Fibrinogen concentration was measured in plasma by the method of Clauss to examine for baseline differences of fibrinogen concentration. Samples were then standardized to 2.8mg/ml fibrinogen using physiological buffer for each sample prior to fibrinolytic testing using rotational thromboelastometry (ROTEM) to examine for differences of clot lysis not attributable to fibrinogen concentration alone. Clot lysis was examined with ROTEM extrinsic pathway activation in the presence of 0, 0.5, and 1.0g/ml of tissue plasminogen activator (tPA). Two-way repeated measures analysis of variance was used to determine the effects of tPA and study group on ROTEM parameters. N=49 Thai samples were compared with N=58 SEA samples. Mean (SD) fibrinogen concentration was significantly increased for the Thai group at 4.03 (0.79)mg/ml vs. the SEA group at 3.66 (0.70)mg/ml (t test P=0.014). After standardization of all samples to equivalent fibrinogen concentration, there were no differences in clot formation between groups without tPA. There was a significant effect of increasing tPA concentration on all ROTEM parameters except for clotting time. There were significant individual differences for amplitude at 10min and lysis onset time, where amplitude at 10min was significantly increased and lysis onset time was significantly prolonged for Thai vs. SEA at tPA concentrations of 0.5 and 1.0g/ml. Variability in thrombosis and hemostasis in Asians vs. other populations is likely to involve differences of fibrinogen concentration and regulation of clot lysis.

INTRODUCTION: Asian women suffer the largest proportion of the world's maternal deaths. To reduce this, policymakers and healthcare providers must encourage women with traditionally low rates of maternal health care utilization to access services. OBJECTIVE: The purpose of this study is to provide a comprehensive review of the most common traditional practices in Asia relating to pregnancy, childbirth and the postpartum period. DESIGN: We conducted a literature search of articles: a) focusing on Asia; b) relating to pregnancy, childbirth or postpartum, c) relating to traditional beliefs and/ or cultural practices; and 4) published in English in the year 2000 or more recently. FINDINGS: A total of 74 articles are included in this review; 20 articles related to pregnancy, 44 to childbirth, and 45 to postpartum. More than one-half ( 38) of the articles focused on South Asia and 13 related to China. In the pregnancy category, the majority of the studies focused on dietary recommendations and behavioral taboos. For the childbirth category, many articles examined beliefs and practices that helped to explain women's aversion to institutional births, such as preference for traditional birth positions, and fear of medical interventions. In the postpartum period, confinement was common because postpartum women were perceived to be weak, fragile and vulnerable to illness. Other prevalent beliefs and practices across Asian countries included massage, the state of pollution after childbirth, the use of traditional healers and traditional medicine and herbs, beliefs relating to hot/cold imbalance, behavioral taboos, magic, and superstition. KEY CONCLUSIONS: Many Asian women continue to practice a wide range of traditional beliefs and practices during pregnancy, childbirth, and the postpartum period. More information is needed on the benefits of formal maternal healthcare services; such educational programs should be geared towards not only women but also husbands, parents, and in-laws. By recognizing and appreciating common local beliefs, providers can be better positioned to provide culturally competent care. Instead of reducing the choices available to women during the birth experience, providers should understand, respect, and integrate cultural interpretations of childbirth and the needs of women and their families.

Upstream oil extraction, which includes exploration and operation to bring crude oil to the surface, frequently occurs near human populations. There are approximately 40,000 oil fields globally and 6 million people that live or work nearby. Oil extraction can impact local soil, water, and air, which in turn can influence community health. As oil resources are increasingly being extracted near human populations, we highlight the current scope of scientific knowledge regarding potential community health impacts with the aim to help identify scientific gaps and inform policy discussions surrounding oil drilling operations. In this review, we assess the wide range of both direct and indirect impacts that oil drilling operations can have on human health, with specific emphasis on understanding the body of scientific literature to assess potential environmental and health risks to residents living near active onshore oil extraction sites. From an initial literature search capturing 2236 studies, we identified 22 human studies, including 5 occupational studies, 5 animal studies, 6 experimental studies and 31 oil drilling-related exposure studies relevant to the scope of this review. The current evidence suggests potential health impacts due to exposure to upstream oil extraction, such as cancer, liver damage, immunodeficiency, and neurological symptoms. Adverse impacts to soil, air, and water quality in oil drilling regions were also identified. Improved characterization of exposures by community health studies and further study of the chemical mixtures associated with oil extraction will be critical to determining the full range of health risks to communities living near oil extraction.

Therapeutic polymers have the potential to improve the standard of care for hemorrhage, or uncontrolled bleeding, as synthetic hemostats. PolySTAT, a fibrin-crosslinking peptide-polymer conjugate, has the capacity to rescue fibrin clot formation and improve survival in a model of acute traumatic bleeding. PolySTAT consists of a synthetic polymer backbone to which targeting fibrin-binding peptides are linked. For translation of PolySTAT, the optimal valency of peptides must be determined. Grafting of fibrin-binding peptides to the poly(hydroxyethyl methacrylate)-based backbone was controlled to produce peptide valencies ranging from 0 to 10 peptides per polymer. PolySTATs with valencies of ≈4 or greater resulted in increased clot firmness, kinetics, and decreased breakdown as measured by thromboelastometry. A valency of ≈4 increased clot firmness 57% and decreased clot breakdown 69% compared to phosphate-buffered saline. This trend was characterized by neutron scattering, which probed the structure of clots formed in the presence of PolySTAT. Finally, PolySTAT with valencies of 4 (100% survival; p = 0.013) and 8 (80% survival; p = 0.063) improved survival compared to an albumin control in a femoral artery injury model (20% survival). This work demonstrates tunability of hemostatic polymers and the ability of in vitro assays to predict in vivo efficacy.

Event Abstract Back to Event Self-propelling particles that stop hemorrhage by transporting therapeutics through flowing blood James Baylis1, 2, Ju Hun Yeon1, 3, Mike Lee1, Jeff Yoon1, Max H. Thomson1, 4, Amir Kazerooni1, Alex E. St. John5, Xu Wang5, Esther B. Lim5, Diana Chien5, Anna Lee1, Jesse Q. Zhang1, James M. Piret1, 2, Lindsay S. Machan4, Thomas F. Burke6, Nathan J. White5 and Christian J. Kastrup1, 3 1 University of British Columbia, Michael Smith Laboratories, Canada 2 University of British Columbia, Chemical and Biological Engineering, Canada 3 University of British Columbia, Biochemistry and Molecular Biology, Canada 4 University of British Columbia, Radiology, Canada 5 University of Washington, Emergency Medicine, United States 6 Massachusetts General Hospital, Division of Global Health and Human Rights, United States Introduction: The outward flow of blood during hemorrhage bleeding makes delivering coagulants to the site of bleeding a major challenge, and uncontrolled bleeding is a major cause of surgical complication and death[1],[2]. Self-propelling particles have been proposed as a strategy for transporting cargos against blood flow and have become a promising tool for designing agents which manage hemorrhage[3]. Self-propelling particles which can be loaded with procoagulant cargo can be used to transport these cargoes into sites of bleeding to rapidly halt hemorrage. Materials and Methods: Self-propelling CaCO3 microparticles were synthesized via precipitation and solid-solid mixing with TXA. The velocity of particles propelling through blood and aqueous solutions was measured by optical microscopy. Thrombin was adsorbed onto microparticles by non-specific, aqueous-phase adsorption. Thrombin-loaded, self-propelling CaCO3 microparticles were tested for their ability to clot blood in vitro, in a mouse tail clip model of amputation and in a mouse liver puncture model of surgical bleeding. Self-propelling microparticles with TXA, but without thrombin, were also tested for their ability to reduce clot lysis and bleeding. Results and Discussion: Self-propelling particles consisting of CaCO3 transported against flow through aqueous solutions and whole blood, up to millimetres into vasculature, at velocities of up to 1.5 cm s-1. Self-propelling CaCO3 microparticles, when loaded with thrombin, were an effective hemostatic agent and halted severe hemorrhage in both mouse models of bleeding. These particles were well tolerated and did not elicit excessive inflammation or local or systemic toxicity. Self-propelling CaCO3 microparticles loaded with TXA, but without thrombin, were also effective at reducing clot lysis and bleeding. These self-propelling, hemostatic particles may constitute an effective treatment for multiple bleeding scenarios including battlefield trauma and postpartum hemorrhage. Many medical applications have been proposed for self-propelling particles, and these findings show that self-propelled particles can function in vivo to enhance drug delivery. Conclusion: We have successfully loaded self-propelling particles with TXA with or without thrombin to create two effective hemostatic agents. These particles burrowed into wound sites and reduced bleeding in vivo. This material has promising applications in managing multiple forms of hemorrhage, or for delivering other classes of therapeutics such as fibrinolytics. Charles Haynes; Laura Ho; Esperanza Garcia; Stefanie Novakowski; UBC Animal Care Services; UBC Bioimaging FacilityReferences:[1] Sauaia et al., J Trauma 38, 185-193 (1995).[2] Kragh et al., US Army Med Dep J, 38-48 (2011).[3] Zhao et al., Lab Chip 13, 1930-1936 (2013). Keywords: in vivo, Drug delivery, delivery, Nano/micro particle Conference: 10th World Biomaterials Congress, Montréal, Canada, 17 May - 22 May, 2016. Presentation Type: New Frontier Oral Topic: Biomaterials in wound care Citation: Baylis J, Yeon J, Lee M, Yoon J, Thomson MH, Kazerooni A, St. John AE, Wang X, Lim EB, Chien D, Lee A, Zhang JQ, Piret JM, Machan LS, Burke TF, White NJ and Kastrup CJ (2016). Self-propelling particles that stop hemorrhage by transporting therapeutics through flowing blood. Front. Bioeng. Biotechnol. Conference Abstract: 10th World Biomaterials Congress. doi: 10.3389/conf.FBIOE.2016.01.02397 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 27 Mar 2016; Published Online: 30 Mar 2016. Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers James Baylis Ju Hun Yeon Mike Lee Jeff Yoon Max H Thomson Amir Kazerooni Alex E St. John Xu Wang Esther B Lim Diana Chien Anna Lee Jesse Q Zhang James M Piret Lindsay S Machan Thomas F Burke Nathan J White Christian J Kastrup Google James Baylis Ju Hun Yeon Mike Lee Jeff Yoon Max H Thomson Amir Kazerooni Alex E St. John Xu Wang Esther B Lim Diana Chien Anna Lee Jesse Q Zhang James M Piret Lindsay S Machan Thomas F Burke Nathan J White Christian J Kastrup Google Scholar James Baylis Ju Hun Yeon Mike Lee Jeff Yoon Max H Thomson Amir Kazerooni Alex E St. John Xu Wang Esther B Lim Diana Chien Anna Lee Jesse Q Zhang James M Piret Lindsay S Machan Thomas F Burke Nathan J White Christian J Kastrup PubMed James Baylis Ju Hun Yeon Mike Lee Jeff Yoon Max H Thomson Amir Kazerooni Alex E St. John Xu Wang Esther B Lim Diana Chien Anna Lee Jesse Q Zhang James M Piret Lindsay S Machan Thomas F Burke Nathan J White Christian J Kastrup Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. 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Event Abstract Back to Event Gauze with self-propelling microparticles containing thrombin and tranexamic acid drastically improved survival in a swine model of lethal hemorrhage Alex St. John1, James R. Baylis2, Xu Wang1, Esther B. Lim1, Matt L. Statz1, Diana Chien1, Susan A. Stern1, Christian J. Kastrup2 and Nathan J. White1 1 University of Washington, Emergency Medicine, United States 2 University of British Columbia, Michael Smith Laboratories, Canada Introduction: Severe bleeding from large arterial wounds is a leading cause of death after trauma. Hemostatic gauzes containing coagulation activators are currently used to pack and compress wounds but are less effective in anatomical locations where compression cannot be performed, likely because their activators are pushed away from the site of vessel injury by the hemorrhaging blood. Gauze impregnated with self-propelling microparticles that disperse hemostatic activators throughout the wound, including upstream against hemorrhage flow, may be useful in these situations. Methods: A self-propelling hemostatic bandage was created by binding thrombin to calcium carbonate microparticles and coating these particles on cotton bandage in the presence of solid protonated tranexamic acid (TXA). Contact with blood causes brisk release of CO2 and propulsion of microparticles against flowing blood to deliver the thrombin and induce hemostasis. Non-protonated TXA was substituted to form a non-propelling control. Bleeding was induced in 29 immature female swine using a 5 mm femoral arteriotomy. Pigs were randomized into 1 of 4 packing interventions without wound compression: negative control, kaolin hemostatic gauze control (Combat Gauze™) (KG), propelled thrombin gauze (PTG), or non-propelled thrombin gauze control (NPTG). All animals then received intravenous fluids to restore blood pressure for up to 3 hours. Survival was compared using Kaplan-Meier log rank, and continuous variables (i.e., blood loss and laboratory values) were compared using repeated measures ANOVA. Results: Survival was improved with PTG (3-hr survival: 8/8, 100%) compared to KG (3/8, 37.5%, p=0.01) and compared to NPTG (2/8, 25.0%, p=0.01). Total and post-intervention external blood loss were similar in all gauze groups (p>0.05). Thromboelastogram maximum amplitude was higher with PTG compared to NPTG at 150 minutes but was otherwise not significantly different. Fibrinogen concentration did not differ across groups. Discussion: Propelled thrombin gauze improved survival in this lethal bleeding model. Self-propelling particles could be used to deliver a number of pro-thrombotic or wound-healing agents throughout an actively hemorrhaging wound to promote hemostasis and recovery. Keywords: Drug delivery, biomaterial, medical application, Bioactive molecule Conference: 10th World Biomaterials Congress, Montréal, Canada, 17 May - 22 May, 2016. Presentation Type: Poster Topic: Biomaterials in thrombosis and hemostasis Citation: St. John A, Baylis JR, Wang X, Lim EB, Statz ML, Chien D, Stern SA, Kastrup CJ and White NJ (2016). Gauze with self-propelling microparticles containing thrombin and tranexamic acid drastically improved survival in a swine model of lethal hemorrhage. Front. Bioeng. Biotechnol. Conference Abstract: 10th World Biomaterials Congress. doi: 10.3389/conf.FBIOE.2016.01.02418 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 27 Mar 2016; Published Online: 30 Mar 2016. Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Alex St. John James R Baylis Xu Wang Esther B Lim Matt L Statz Diana Chien Susan A Stern Christian J Kastrup Nathan J White Google Alex St. John James R Baylis Xu Wang Esther B Lim Matt L Statz Diana Chien Susan A Stern Christian J Kastrup Nathan J White Google Scholar Alex St. John James R Baylis Xu Wang Esther B Lim Matt L Statz Diana Chien Susan A Stern Christian J Kastrup Nathan J White PubMed Alex St. John James R Baylis Xu Wang Esther B Lim Matt L Statz Diana Chien Susan A Stern Christian J Kastrup Nathan J White Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

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.