{
  "abstract": "Introduction Traumatic haemorrhagic shock (THS) is the major mechanism of death in ‘potentially survivable’ combat injuries. Indeed, during modern conflicts, 90% of preventable deaths are of haemorrhagic origin, and about 70% of deaths during the first week after trauma are due to Multiple Organs Failure (MOF). 1 2 It highlights the need for NATO armed forces to dedicate research programs to new therapeutic strategies to mitigate THS consequences, particularly in the pre-hospital environment.THS induces deregulation of major pathophysiological crossroads (inflammation, endotheliopathy, coagulopathy…) which contribute to early cellular and tissue damage. Current intensive care technics are based on haemorrhage control, fluid replacement, vasoactive amines and blood products administration. Unfortunately, these approaches are not sufficient to prevent the onset of MOF. Here, we explore a solution to develop an innovative product to prevent MOF development and finally reducing morbidity and mortality. Mesenchymal Stromal Cells (MSC) are powerful homeostasis controller. As we previously shown, IL1β primed MSC (MSCp) are able to limit MOF by reducing immunological and endothelial dysfunctions in a rodent model.3 4 However, it is currently not possible to use cell therapy in military operations. The efficiency of MSC is mainly attributed to the secretion of a wide range of acellular products composed of soluble factors (SF) and extracellular vesicles (EV). These products could be easier to use in non-permissive environments like high intensity conflicts.Material and Methods Culture supernatant were obtained from 72h of secretion of MSCp. We have adapted a Tangential Flow Filtration (TFF) method already used in the pharmaceutical industry, to purify/concentrate large volumes of secretome. 5 A morphological (cryoelectronic microscopy), biophysical (number, size, cytometry analysis), molecular (proteomic analysis) and in vitro functional characterization by anti-inflammatory and immunomodulation assays, was carried out on the acellular products. We developed a THS model in rat, haemorrhagic shock was induced by blood spoliation at a fixed mean arterial pressure (35mmHg) and rhabdomyolysis via glycerol intramuscular injection. Haemorrhage and trauma were followed by resuscitation with lactate ringer and transfusion of spoliated blood. Acellular products were injected intravenously at the beginning of the resuscitation phase. Our outcomes are based on biological, histological, protein and transcript analyses 6 hours after the start of resuscitation.Results As expected EVs had lipids bilayers membranes with mean diameter around 130 nm, they expressed tetraspanin and MSC specific markers. Proteomic analysis revealed enrichment protein involves in several physiological domains like immune system (Neutrophil degranulation, IL10 and IL12 signalling), haemostasis (Platelet degranulation, activation and aggregation), extracellular matrix organization (Metalloprotease activation, collagen degradation) or cellular response to stimuli (ROS detoxification). This enrichment characterized tissue repair ability.Acellular products exert strong anti-inflammatory activity on monocytes and immunomodulatory effect on T cells in vitro, which is consistent with proteomic data. In vivo experiments are ongoing but already showed that these products have no toxic effect.Abstract A02 Figure 1Conclusion These new acellular therapeutic products, classified as biological drugs, can, unlike cells, be already prepared in large quantities, are easy to store, transport and could be immediately available on the battlefield. They represent a tremendous opportunity in combat casualty care.References Eastridge BJ, Mabry RL, Seguin P, Cantrell J, Tops T, Uribe P, et al. Death on the battlefield (2001–2011): implications for the future of combat casualty care. J Trauma Acute Care Surg. 2012 Dec 1;73(6).Sobrino J, Shafi S. Timing and causes of death after injuries. Proc (Bayl Univ Med Cent). 2013 Apr;26(2):120–3.Aussel C, Baudry N, Grosbot M, Caron C, Vicaut E, Banzet S, et al. IL-1β primed mesenchymal stromal cells moderate hemorrhagic shock-induced organ injuries. Stem Cell Res Ther. 2021 Aug 5;12(1):438.Baudry N, Campeanu A, Aussel C, Doutrelon C, Grosbot M, Banzet S, et al. IL-1β primed mesenchymal stromal cells moderate hemorrhagic shock-induced vascular permeability. J Transl Med. 2024 Dec 24;22(1):1143.Lorenzini B, Peltzer J, Goulinet S, Rival B, Lataillade JJ, Uzan G, et al. Producing vesicle-free cell culture additive for human cells extracellular vesicles manufacturing. Journal of Controlled Release. 2023 Mar 1;355:501–14.Disclosures Authors do not declare any conflicting financial interests.This work was approved by sponsoring authority (Grants from Direction Générale de l’Armement #SAN-1–2320)",
  "authors": [
    {
      "affiliations": [
        "French Armed Forces Biomedical Research Institute (IRBA), Clamart, France",
        "INSERM-MD-U1197, Villejuif, France"
      ],
      "name": "Guillaume Valade"
    },
    {
      "affiliations": [
        "French Armed Forces Biomedical Research Institute (IRBA), Clamart, France",
        "INSERM-MD-U1197, Villejuif, France"
      ],
      "name": "Marion Grosbot"
    },
    {
      "affiliations": [
        "French Armed Forces Biomedical Research Institute (IRBA), Clamart, France",
        "INSERM-MD-U1197, Villejuif, France"
      ],
      "name": "Marine De Taddeo"
    },
    {
      "affiliations": [
        "INSERM-MD-U1197, Villejuif, France"
      ],
      "name": "Sylvie Goulinet"
    },
    {
      "affiliations": [
        "INSERM-MD-U1197, Villejuif, France"
      ],
      "name": "Philippe Mauduit"
    },
    {
      "affiliations": [
        "Université Paris Cité, Proteomics Platform Necker, Structure Fédérative de Recherche Necker, INSERM US24/CNRS UMS3633, 75015 Paris, France"
      ],
      "name": "Vincent Jung"
    },
    {
      "affiliations": [
        "Université Paris Cité, Proteomics Platform Necker, Structure Fédérative de Recherche Necker, INSERM US24/CNRS UMS3633, 75015 Paris, France"
      ],
      "name": "Chiara Guerrera"
    },
    {
      "affiliations": [
        "French Armed Forces Biomedical Research Institute (IRBA), Clamart, France",
        "INSERM-MD-U1197, Villejuif, France"
      ],
      "name": "Sébastien Banzet"
    },
    {
      "affiliations": [
        "French Armed Forces Biomedical Research Institute (IRBA), Clamart, France",
        "INSERM-MD-U1197, Villejuif, France"
      ],
      "name": "Marina Trouillas"
    },
    {
      "affiliations": [
        "French Armed Forces Biomedical Research Institute (IRBA), Clamart, France",
        "INSERM-MD-U1197, Villejuif, France"
      ],
      "name": "Juliette Peltzer"
    }
  ],
  "title": "A02 How to bring biotherapy on battlefield to prevent multiple organ failure during traumatic haemorrhagic shock?",
  "uid": "55ffac95-95f6-555b-91ef-f27b0df7f74a"
}