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  • 1.
    Asif, Sana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Regulation of thromboinflammation in therapeutic medicine: Special focus on surface coating strategies2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Biomaterials are an integral part of modern health care and offer potential treatment modalities to diseases and conditions otherwise intractable. However, the critical issue herein is incompatibility reactions.

    Our innate immune system is fundamental in protection against pathogens and foreign intruders and controls the discrimination between self and non-self. Biomaterials come in contact with blood upon implantation where they are sensed by innate immune mediators which through a cascade of complex, multifaceted reactions induce inflammation as well as thrombosis which may induce biomaterial dysfunction and rejection. This explains why patients undergoing haemodialysis therapy exhibit an increased incidence of whole-body inflammation and other thrombotic events. Similarly, therapeutic cells such as hepatocytes upon implantation initiate an instant blood mediated inflammatory reaction, responsible for cell damage and death via apoptosis.

    In order to achieve safer and more efficient therapeutic interventions,  engineering of materials and cells that can avoid these adverse reactions is essential. Fabrication of biomaterials consisting of  coating of bioinert polymers to avoid immune recognition and activation is a promising approach to modulate immune reactions.

    In this thesis, we have employed a PEG-lipid polymer coating, which intercalates in to biomembranes via hydrophobic interactions and thus shields from immune rejection. Treatment with PEG-lipid not only makes the surface “invisible” to immune cells but it also acts as a filter which prevents entry of immune cells without inducing cytotoxicity. Results from this thesis illustrate that fabrication of bio-surfaces by bio-inert PEG-lipid polymer is a harmless procedure which not  only attenuates thrombo-inflammation but also assist in design of self-tailored materials for a wide range of biomedical applications.

    List of papers
    1. Heparinization of cell surfaces with short pepetide-conjugated PEG-lipid regulates thromboinflammation in thransplantation of human MSCs and hepatocytes
    Open this publication in new window or tab >>Heparinization of cell surfaces with short pepetide-conjugated PEG-lipid regulates thromboinflammation in thransplantation of human MSCs and hepatocytes
    Show others...
    2016 (English)In: Acta Biomaterialia, ISSN 1742-7061, E-ISSN 1878-7568, Vol. 35, p. 194-205Article in journal (Refereed) Published
    Abstract [en]

    Infusion of therapeutic cells into humans is associated with immune responses, including thromboinflammation, which result in a large loss of transplanted cells\ To address these problems, heparinization of the cell surfaces was achieved by a cell-surface modification technique using polyethylene glycol conjugated phospholipid (PEG-lipid) derivatives. A short heparin-binding peptide was conjugated to the PEG-lipid for immobilization of heparin conjugates on the surface of human mesenchymal stem cells (hMSCs) and human hepatocytes. Here three kinds of heparin-binding peptides were used for immobilizing heparin conjugates and examined for the antithrombogenic effects on the cell surface. The heparinized cells were incubated in human whole blood to evaluate their hemocompatibility by measuring blood parameters such as platelet count, coagulation markers, complement markers, and Factor Xa activity. We found that one of the heparin-binding peptides did not show cytotoxicity after the immobilization with heparin conjugates. The degree of binding of the heparin conjugates on the cell surface (analyzed by flow cytometer) depended on the ratio of the active peptide to control peptide. For both human MSCs and hepatocytes in whole-blood experiments, no platelet aggregation was seen in the heparin conjugate-immobilized cell group vs. the controls (non-coated cells or control peptide). Also, the levels of thrombin-antithrombin complex (TAT), C3a, and sC5b-9 were significantly lower than those of the controls, indicating a lower activation of coagulation and complement. Factor Xa analysis indicated that the heparin conjugate was still active on the cell surface at 24 h post-coating. It is possible to immobilize heparin conjugates onto hMSC and human hepatocyte surfaces and thereby protect the cell surfaces from damaging thromboinflammation. Statement of Signigficance We present a promising approach to enhance the biocompatibility of therapeutic cells. Here we used short peptide-conjugated PEG-lipid for cell surface modification and heparin conjugates for the coating of human hepatocytes and MSCs. We screened the short peptides to find higher affinity for heparinization of cell surface and performed hemocompatibility assay of heparinized human hepatocytes and human MSCs in human whole blood. Using heparin-binding peptide with higher affinity, not only coagulation activation but also complement activation was significantly suppressed. Thus, it was possible to protect human hepatocytes and human MSCs from the attack of thromboinflammatory activation, which can contribute to the improvement graft survival.

    Keywords
    Cell surface modification; Heparinization; Thromboinflammation; MSCs; Hepatocyte; Polyethylene glycol-conjugated phospholipid (PEG-lipid)
    National Category
    Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
    Identifiers
    urn:nbn:se:uu:diva-279420 (URN)10.1016/j.actbio.2016.02.018 (DOI)000375162200018 ()26876877 (PubMedID)
    Funder
    Swedish Research CouncilThe Swedish Foundation for International Cooperation in Research and Higher Education (STINT)
    Available from: 2016-03-01 Created: 2016-03-01 Last updated: 2019-12-14Bibliographically approved
    2. Cell Adhesion Induced Using Surface Modification with Cell-Penetrating Peptide-Conjugated Poly(ethylene glycol)-Lipid: A New Cell Glue for 3D Cell-Based Structures
    Open this publication in new window or tab >>Cell Adhesion Induced Using Surface Modification with Cell-Penetrating Peptide-Conjugated Poly(ethylene glycol)-Lipid: A New Cell Glue for 3D Cell-Based Structures
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    2017 (English)In: ACS Applied Materials and Interfaces, ISSN 1944-8244, E-ISSN 1944-8252, Vol. 9, no 1, p. 244-254Article in journal (Refereed) Published
    Abstract [en]

    We synthesized a novel material, cell-penetrating peptide-conjugated poly(ethylene glycol)-lipid (CPP-PEG-lipid), that can induce the adhesion of floating cells. Firm cell adhesion with spreading could be induced by cell surface modification with the CPP-PEG-lipids. Cell adhesion was induced by CPPs but not by any other cationic short peptides we tested. Here, we demonstrated adherence using the floating cell line CCRF-CEM as well as primary human T cells, B cells, erythrocytes, and hepatocytes. As compared to cells grown in suspension, adherent cells were more rapidly induced to attach to substrates with the cell-surface modification. The critical factor for attachment was localization of CPPs at the cell membrane by PEG-lipids with PEG > 20 kDa. These cationic CPPs on PEG chains were able to interact with substrate surfaces such as polystyrene (PS) surfaces, glass surfaces, and PS microfibers that are negatively charged, inducing firm cell adhesion and cell spreading. Also, as opposed to normal cationic peptides that interact strongly with cell membranes, CPPs were less interactive with the cell surfaces because of their cell-penetrating property, making them more available for adhering cells to the substrate surface. No effects on cell viability or cell proliferation were observed after the induction of cell adhesion. With this technique, cells could be easily immobilized onto PS microfibers, an important step in fabricating 3D cell-based structures. Cells immobilized onto 3D PS microfibers were alive, and human hepatocytes showed normal production of urea and albumin on the microfibers. This method is novel in inducing firm cell adhesion via a one-step treatment.

    Keywords
    3D structure, cell adhesion, cell surface modification, cell-penetrating peptide (CPP), poly(ethylene glycol)-conjugated phospholipid (PEG−lipid)
    National Category
    Clinical Medicine
    Identifiers
    urn:nbn:se:uu:diva-373991 (URN)10.1021/acsami.6b14584 (DOI)000392037400031 ()27976850 (PubMedID)
    Funder
    The Swedish Foundation for International Cooperation in Research and Higher Education (STINT)
    Available from: 2019-01-17 Created: 2019-01-17 Last updated: 2019-12-14Bibliographically approved
    3. Validation of an MPC polymer coating to attenuate surface- induced cross-talk between the complement and coagulation systems in whole blood in in vitro and in vivo models
    Open this publication in new window or tab >>Validation of an MPC polymer coating to attenuate surface- induced cross-talk between the complement and coagulation systems in whole blood in in vitro and in vivo models
    Show others...
    2019 (English)In: Macromolecular Bioscience, ISSN 1616-5187, E-ISSN 1616-5195, Vol. 19, no 5, article id 1800485Article in journal (Refereed) Published
    Abstract [en]

    Artificial surfaces that come into contact with blood induce an immediate activation of the cascade systems of the blood, leading to a thrombotic and/or inflammatory response that can eventually cause damage to the biomaterial or the patient, or to both. Heparin coating has been used to improve hemocompatibility, and another approach is 2-methacryloyloxyethyl phosphorylcholine (MPC)-based polymer coatings. Here, the aim is to evaluate the hemocompatibility of MPC polymer coating by studying the interactions with coagulation and complement systems using human blood in vitro model and pig in vivo model. The stability of the coatings is investigated in vitro and MPC polymer-coated catheters are tested in vivo by insertion into the external jugular vein of pigs to monitor the catheters' antithrombotic properties. There is no significant activation of platelets or of the coagulation and complement systems in the MPC polymer-coated one, which was superior in hemocompatibility to non-coated matrix surfaces. The protective effect of the MPC polymer coat does not decline after incubation in human plasma for up to 2 weeks. With MPC polymer-coated catheters, it is possible to easily draw blood from pig for 4 days in contrast to the case for non-coated catheters, in which substantial clotting is seen.

    Place, publisher, year, edition, pages
    Wiley-VCH Verlagsgesellschaft, 2019
    Keywords
    blood compatibility, blood model systems, coagulation system, complement system, heparin coat, MPC polymer coat
    National Category
    Clinical Laboratory Medicine Biomaterials Science
    Identifiers
    urn:nbn:se:uu:diva-374785 (URN)10.1002/mabi.201800485 (DOI)000471340300015 ()30786149 (PubMedID)
    Funder
    Swedish Research Council, 2016-2075-5.1Swedish Research Council, 2016-04519The Swedish Foundation for International Cooperation in Research and Higher Education (STINT)
    Note

    Kazuhiko Ishihara har tillkommit som författare sedan posten lades in som manuskript.

    Available from: 2019-01-24 Created: 2019-01-24 Last updated: 2019-12-14Bibliographically approved
  • 2.
    Asif, Sana
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Asawa, Kenta
    Department of Bioengineering, The University of Tokyo, 7‐3‐1 Hongo, Bunkyo‐ku, Tokyo, 113–8656 Japan.
    Yuuki, Inoue
    Department of Bioengineering, The University of Tokyo, 7‐3‐1 Hongo, Bunkyo‐ku, Tokyo, 113–8656 Japan.
    Ishihara, Kazuhiko
    Department of Bioengineering, The University of Tokyo, 7‐3‐1 Hongo, Bunkyo‐ku, Tokyo, 113–8656 Japan.
    Lindell, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Oral and Maxillofacial Surgery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Holmgren, Robin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Ryden, Anneli
    Department of Clinical Sciences, Faculty of Veterinary Medicine and Animal Science, Swedish University of Agricultural Sciences, Almas Allé 8, 750 07 Uppsala, Sweden.
    Jensen-Waern, Marianne
    Department of Clinical Sciences, Faculty of Veterinary Medicine and Animal Science, Swedish University of Agricultural Sciences, Almas Allé 8, 750 07 Uppsala, Sweden.
    Teramura, Yuji
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Department of Bioengineering, The University of Tokyo, Tokyo, Japan.
    Nilsson Ekdahl, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Linnaeus Center of Biomaterials Chemistry, Linnaeus University, Kalmar, Sweden.
    Validation of an MPC polymer coating to attenuate surface- induced cross-talk between the complement and coagulation systems in whole blood in in vitro and in vivo models2019In: Macromolecular Bioscience, ISSN 1616-5187, E-ISSN 1616-5195, Vol. 19, no 5, article id 1800485Article in journal (Refereed)
    Abstract [en]

    Artificial surfaces that come into contact with blood induce an immediate activation of the cascade systems of the blood, leading to a thrombotic and/or inflammatory response that can eventually cause damage to the biomaterial or the patient, or to both. Heparin coating has been used to improve hemocompatibility, and another approach is 2-methacryloyloxyethyl phosphorylcholine (MPC)-based polymer coatings. Here, the aim is to evaluate the hemocompatibility of MPC polymer coating by studying the interactions with coagulation and complement systems using human blood in vitro model and pig in vivo model. The stability of the coatings is investigated in vitro and MPC polymer-coated catheters are tested in vivo by insertion into the external jugular vein of pigs to monitor the catheters' antithrombotic properties. There is no significant activation of platelets or of the coagulation and complement systems in the MPC polymer-coated one, which was superior in hemocompatibility to non-coated matrix surfaces. The protective effect of the MPC polymer coat does not decline after incubation in human plasma for up to 2 weeks. With MPC polymer-coated catheters, it is possible to easily draw blood from pig for 4 days in contrast to the case for non-coated catheters, in which substantial clotting is seen.

  • 3.
    Asif, Sana
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Asawa, Kenta
    Yuuki, Inoue
    Kazuhiko, Ishihara2
    Lindell, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Oral and Maxillofacial Surgery.
    Holmgren, Robin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Ryden, Anneli
    Wearn, Marinne Jensen
    Teramura, Yuji
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Nilsson Ekdahl, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Solid State Physics.
    Validation of an MPC polymer coating to reduce surface-induced cascade system activation in whole blood in in vitroand in vivo modelsManuscript (preprint) (Other academic)
    Abstract [en]

    ABSTRACT

    Background: Artificial surfaces that come into contact with blood (e.g., when used in various forms of biomedical device) induce an immediate activation of the cascade systems of the blood, the coagulation and complement systems. These reactions may lead to a thrombotic and/or inflammatory response that can eventually cause damage to the biomaterial or the patient, or to both. Multiple strategies to dampen these reactions have been employed, with heparin conjugation to the material surface being the most successfulthus far. Another approach to improving hemocompatibility is to use 2-methacryloyloxyethyl phosphorylcholine (MPC)-based polymer coatings.

    Experimental: In the present study, we evaluated the effectiveness of MPC polymer coating and compared it to a commercially available heparin coating in various in vitromodels using fresh human blood with the aim to replace the costly heparin-coated equipment with the more economic MPC. We then investigated the stability of the various coatings in human plasma in vitrofor 2 weeks. Finally, we inserted MPC polymer-coated catheters into the external jugular vein of pigs and monitored the catheters’ antithrombotic properties for 4 days.

    Results: 1) There was no significant activation of platelets and of the coagulation and complement systems on the MPC polymer-coated or the commercially available heparin surface. 2) Both coats were superior in hemocompatibility to non-coated matrix surfaces. 3) The protective effect of the MPC polymer coat did not decline after incubation in plasma for up to 2 weeks. 4) With MPC polymer-coated catheters, it was possible to easily draw blood from experimental animals for 4 days, in contrast to the case for heparin-flushed commercially available non-coated catheters, in which substantial clotting was seen.

  • 4.
    Asif, Sana
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Ekdahl, Kristina N
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Linnæus Center of Biomaterials Chemistry, Linnæus University, SE-391 82 Kalmar, Sweden.
    Fromell, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Gustafson, Elisabet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Paediatric Surgery.
    Barbu, Andreea
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Le Bland, Katarina
    Division of Clinical Immunology and Transfusion Medicine, Department of Laboratory Medicine, Karolinska Institute, and Hematology and Regenerat ive Medicine Centre at Karolinska University Hospital Huddinge, SE-141 86 Stockholm, Sweden.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Teramura, Yuji
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Department of Bioengineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
    Heparinization of cell surfaces with short pepetide-conjugated PEG-lipid regulates thromboinflammation in thransplantation of human MSCs and hepatocytes2016In: Acta Biomaterialia, ISSN 1742-7061, E-ISSN 1878-7568, Vol. 35, p. 194-205Article in journal (Refereed)
    Abstract [en]

    Infusion of therapeutic cells into humans is associated with immune responses, including thromboinflammation, which result in a large loss of transplanted cells\ To address these problems, heparinization of the cell surfaces was achieved by a cell-surface modification technique using polyethylene glycol conjugated phospholipid (PEG-lipid) derivatives. A short heparin-binding peptide was conjugated to the PEG-lipid for immobilization of heparin conjugates on the surface of human mesenchymal stem cells (hMSCs) and human hepatocytes. Here three kinds of heparin-binding peptides were used for immobilizing heparin conjugates and examined for the antithrombogenic effects on the cell surface. The heparinized cells were incubated in human whole blood to evaluate their hemocompatibility by measuring blood parameters such as platelet count, coagulation markers, complement markers, and Factor Xa activity. We found that one of the heparin-binding peptides did not show cytotoxicity after the immobilization with heparin conjugates. The degree of binding of the heparin conjugates on the cell surface (analyzed by flow cytometer) depended on the ratio of the active peptide to control peptide. For both human MSCs and hepatocytes in whole-blood experiments, no platelet aggregation was seen in the heparin conjugate-immobilized cell group vs. the controls (non-coated cells or control peptide). Also, the levels of thrombin-antithrombin complex (TAT), C3a, and sC5b-9 were significantly lower than those of the controls, indicating a lower activation of coagulation and complement. Factor Xa analysis indicated that the heparin conjugate was still active on the cell surface at 24 h post-coating. It is possible to immobilize heparin conjugates onto hMSC and human hepatocyte surfaces and thereby protect the cell surfaces from damaging thromboinflammation. Statement of Signigficance We present a promising approach to enhance the biocompatibility of therapeutic cells. Here we used short peptide-conjugated PEG-lipid for cell surface modification and heparin conjugates for the coating of human hepatocytes and MSCs. We screened the short peptides to find higher affinity for heparinization of cell surface and performed hemocompatibility assay of heparinized human hepatocytes and human MSCs in human whole blood. Using heparin-binding peptide with higher affinity, not only coagulation activation but also complement activation was significantly suppressed. Thus, it was possible to protect human hepatocytes and human MSCs from the attack of thromboinflammatory activation, which can contribute to the improvement graft survival.

  • 5.
    Asif, Sana
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Sedigh, Amir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Nordström, Johan
    Department of Transplantation Surgery, Karolinska University Hospital, Stockholm, Sweden.
    Brandhorst, Heide
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Jorns, Carl
    Department of Transplantation Surgery, Karolinska University Hospital, Stockholm, Sweden.
    Lorant, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Larsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Magnusson, Peetra U.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Nowak, Greg
    Department of Transplantation Surgery, Karolinska University Hospital, Stockholm, Sweden.
    Theisinger, Sonja
    Novaliq GmbH, Heidelberg, Germany.
    Hoeger, Simone
    Department of Nephrology, Endocrinology and Rheumatology, University Medical Center Mannheim, Mannheim, Germany.
    Wennberg, Lars
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Brandhorst, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Oxygen-charged HTK-F6H8 emulsion reduces ischemia: reperfusion injury in kidneys from brain-dead pigs2012In: Journal of Surgical Research, ISSN 0022-4804, E-ISSN 1095-8673, Vol. 178, no 2, p. 959-967Article in journal (Refereed)
    Abstract [en]

    Background:

    Prolonged cold ischemia is frequently associated with a greater risk of delayed graft function and enhanced graft failure. We hypothesized that media, combining a high oxygen-dissolving capacity with specific qualities of organ preservation solutions, would be more efficient in reducing immediate ischemia-reperfusion injury from organs stored long term compared with standard preservation media.

    Methods:

    Kidneys retrieved from brain-dead pigs were flushed using either cold histidine-tryptophan-ketoglutarate (HTK) or oxygen-precharged emulsion composed of 75% HTK and 25% perfluorohexyloctane. After 18 h of cold ischemia the kidneys were transplanted into allogeneic recipients and assessed for adenosine triphosphate content, morphology, and expression of genes related to hypoxia, environmental stress, inflammation, and apoptosis.

    Results:

    Compared with HTK-flushed kidneys, organs preserved using oxygen-precharged HTK-perfluorohexyloctane emulsion had increased elevated adenosine triphosphate content and a significantly lower gene expression of hypoxia inducible factor-1 alpha, vascular endothelial growth factor, interleukin-1 alpha, tumor necrosis factor-alpha, interferon-alpha, JNK-1, p38, cytochrome-c, Bax, caspase-8, and caspase-3 at all time points assessed. In contrast, the mRNA expression of Bcl-2 was significantly increased.

    Conclusions:

    The present study has demonstrated that in brain-dead pigs the perfusion of kidneys with oxygen-precharged HTK-perfluorohexyloctane emulsion results in significantly reduced inflammation, hypoxic injury, and apoptosis and cellular integrity and energy content are well maintained. Histologic examination revealed less tubular, vascular, and glomerular changes in the emulsion-perfused tissue compared with the HTK-perfused counterparts. The concept of perfusing organs with oxygen-precharged emulsion based on organ preservation media represents an efficient alternative for improved organ preservation.

  • 6.
    Brandhorst, Heide
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Asif, Sana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Andersson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Moench, Johanna
    Serva Electrophoresis GmbH, Uetersen, Germany..
    Friedrich, Olaf
    Nordmark Arzneimittel GmbH & Co KG, Uetersen, Germany..
    Raemsch-Guenther, Nicole
    Serva Electrophoresis GmbH, Uetersen, Germany..
    Raemsch, Christian
    Nordmark Arzneimittel GmbH & Co KG, Uetersen, Germany..
    Steffens, Melanie
    Serva Electrophoresis GmbH, Uetersen, Germany..
    Lambrecht, Joerg
    Nordmark Arzneimittel GmbH & Co KG, Uetersen, Germany..
    Schraeder, Thomas
    Nordmark Arzneimittel GmbH & Co KG, Uetersen, Germany..
    Kurfuerst, Manfred
    Nordmark Arzneimittel GmbH & Co KG, Uetersen, Germany..
    Andersson, Helene H.
    Univ Hosp, Dept Nephrol & Transplantat, Malmo, Sweden..
    Felldin, Marie
    Univ Hosp, Dept Transplantat, Gothenburg, Sweden..
    Foss, Aksel
    Univ Oslo, Rikshosp, Oslo Univ Hosp, Div Surg,Sect Transplantat, N-0027 Oslo, Norway..
    Salmela, Kaija
    Univ Helsinki, Surg Hosp, Div Transplantat, Helsinki, Finland..
    Tibell, Annika
    Karolinska Inst, Div Transplantat Surg, CLINTEC, Stockholm, Sweden..
    Tufveson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Brandhorst, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    The Effect of Truncated Collagenase Class I Isomers on Human Islet Isolation Outcome2010In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 90, no 3, p. 334-335Article in journal (Refereed)
  • 7.
    Brandhorst, Heide
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Asif, Sana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Andersson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Theisinger, Bastian
    Andersson, Helene H
    Felldin, Maria
    Foss, Aksel
    Salmela, Kaija
    Tibell, Annika
    Tufveson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Brandhorst, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    A new oxygen carrier for improved long-term storage of human pancreata before islet isolation2010In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 89, no 2, p. 155-60Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Pancreas oxygenation during cold storage has been established in islet isolation and transplantation to prevent ischemic tissue damage using perfluorodecalin (PFD) as hyperoxygen carrier. However, studies in humans and pigs provided conflicting results about the efficiency of PFD for pancreas oxygenation. The aim of this study was to compare PFD with a newly developed oxygen carrier composed of perfluorohexyloctane and polydimethylsiloxane 5 (F6H8S5) for long-term storage of human pancreata.

    METHODS: After 24-hr storage in preoxygenated PFD or F6H8S5, pancreata were processed using Liberase HI for pancreas dissociation and a Ficoll gradient for islet purification. Islet quality assessment was performed measuring glucose-stimulated insulin release, viability, islet ATP content, and posttransplant function in diabetic nude mice.

    RESULTS: Compared with PFD, F6H8S5 significantly increased the intrapancreatic partial oxygen pressure and islet ATP content. This corresponded to an increase of islet yield, recovery after culture, glucose stimulation index, viability, and improved graft function in diabetic nude mice.

    CONCLUSIONS: The present findings indicate clearly that F6H8S5 improves isolation outcome after prolonged ischemia compared with PFD. This observation seems to be related to the significant lipophilicity and almost pancreas-specific density of F6H8S5. Moreover, these characteristics facilitate pancreas shipment without using custom-made transport vessels as required for PFD.

  • 8.
    Caballero-Corbalan, José
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Brandhorst, Heide
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Asif, Sana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Engelse, Marten
    Leiden Univ, Med Ctr, Dept Nephrol, Leiden, Netherlands.
    de Koning, Eelco
    Leiden Univ, Med Ctr, Dept Nephrol, Leiden, Netherlands.
    Pattou, Francois
    Univ Hosp, INSERM ERIT M 0106 Diabet Cell Therapy, Lille, France.
    Kerr-Conte, Julie
    Univ Hosp, INSERM ERIT M 0106 Diabet Cell Therapy, Lille, France.
    Brandhorst, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Mammalian Tissue-Free Liberase: A New GMP-Graded Enzyme Blend for Human Islet Isolation2010In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 90, no 3, p. 332-333Article in journal (Refereed)
  • 9.
    Gustafson, Elisabet
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Paediatric Surgery.
    Asif, Sana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Kozarcanin, Huda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Meurling, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Ekdahl, Kristina Nilsson
    Linnaeus Univ, Linnaeus Ctr Biomat Chem, Kalmar, Sweden.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Control of IBMIR induced by fresh and cryopreserved hepatocytes by low molecular weight dextran sulfate2017In: Cell Transplantation, ISSN 0963-6897, E-ISSN 1555-3892, Vol. 26, no 1, p. 71-81Article in journal (Refereed)
    Abstract [en]

    Rapid destruction of hepatocytes after hepatocyte transplantation has hampered the application of this procedure clinically. The instant blood-mediated inflammatory reaction (IBMIR) is a plausible underlying cause for this cell loss. The present study was designed to evaluate the capacity of low molecular weight dextran sulfate (LMW-DS) to control these initial reactions from the innate immune system. Fresh and cryopreserved hepatocytes were tested in an in vitro whole-blood model using ABO-compatible blood. The ability to elicit IBMIR and the capacity of LMW-DS (100 mu g/ml) to attenuate the degree of activation of the cascade systems were monitored. The effect was also compared to conventional anticoagulant therapy using unfractionated heparin (1 IU/ml). Both fresh and freeze thawed hepatocytes elicited IBMIR to the same extent. LMW-DS reduced the platelet loss and maintained the cell counts at the same degree as unfractionated heparin, but controlled the coagulation and complement systems significantly more efficiently than heparin. LMW-DS also attenuated the IBMIR elicited by freeze thawed cells. Therefore, LMW-DS inhibits the cascade systems and maintains the cell counts in blood triggered by both fresh and cryopreserved hepatocytes in direct contact with ABO-matched blood. LMW-DS at a previously used and clinically applicable concentration (100 mu g/ml) inhibits IBMIR in vitro and is therefore a potential IBMIR inhibitor in hepatocyte transplantation.

  • 10.
    Nilsson, Bo
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Asif, Sana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Ekdahl N., Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Linnaeus Univ, Linnaeus Ctr Biomat Chem, Kalmar, Sweden.
    Manell, Elin
    Swedish Univ Agr Sci, Fac Vet Med & Anim Sci, Dept Clin Sci, Uppsala, Sweden.
    Biglarnia, Alireza
    Skane Univ Hosp, Dept Transplantat, Malmo, Sweden.
    Jensen-Waern, Marianne
    Swedish Univ Agr Sci, Fac Vet Med & Anim Sci, Dept Clin Sci, Uppsala, Sweden.
    Teramura, Yuji
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Univ Tokyo, Dept Bioengn, Tokyo, Japan.
    A protective role of complement regulators linked to a PEG phospholipid construct in reducing ischemic reperfusion injury in transplantation2017In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 89, p. 208-208Article in journal (Other academic)
  • 11.
    Nilsson Ekdahl, Kristina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Teramura, Yuji
    Asif, Sana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Jonsson, Nina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Linnæus Center of Biomaterials Chemistry, Linnæus University, Kalmar, Sweden.
    Magnusson, Peetra
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Thromboinflammation in Therapeutic Medicine2015In: Advances in Experimental Medicine and Biology, ISSN 0065-2598, E-ISSN 2214-8019, Vol. 865, p. 3-17Article, review/survey (Refereed)
    Abstract [en]

    Thromboinflammation is primarily triggered by the humoral innate immune system, which mainly consists of the cascade systems of the blood, i.e., the complement, contact/coagulation and fibrinolytic systems. Activation of these systems subsequently induces activation of endothelial cells, leukocytes and platelets, finally resulting in thrombotic and inflammatory reactions. Such reactions are triggered by a number of medical procedures, e.g., treatment with biomaterials or drug delivery devices as well as in transplantation with cells, cell clusters or whole vascularized organs. Here, we (1) describe basic mechanisms for thromboinflammation; (2) review thromboinflammatory reactions in therapeutic medicine; and (3) discuss emerging strategies to dampen thromboinflammation.

  • 12.
    Nilsson Ekdahl, Kristina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Linnæus Center of Biomaterials Chemistry, Linnæus University, Kalmar, Sweden.
    Teramura, Yuji
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Department of Bioengineering, The University of Tokyo, Tokyo, Japan.
    Hamad, Osama A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Asif, Sana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Dührkop, Claudia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Fromell, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Gustafson, Elisabet K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Pediatric Surgery.
    Hong, Jaan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Kozarcanin, Huda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Magnusson, Peetra
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Huber-Lang, Markus
    Department of Orthopedic Trauma, Hand, Plastic and Reconstructive Surgery, University of Ulm, Ulm, Germany.
    Garred, Peter
    Laboratory of Molecular Medicine, Department of Clinical Immunology, Section 7631, Faculty of Health and Medical Sciences, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Dangerous liaisons: complement, coagulation, and kallikrein/kinin cross-talk act as a linchpin in the events leading to thromboinflammation2016In: Immunological Reviews, ISSN 0105-2896, E-ISSN 1600-065X, Vol. 274, no 1, p. 245-269Article in journal (Refereed)
    Abstract [en]

    Innate immunity is fundamental to our defense against microorganisms. Physiologically, the intravascular innate immune system acts as a purging system that identifies and removes foreign substances leading to thromboinflammatory responses, tissue remodeling, and repair. It is also a key contributor to the adverse effects observed in many diseases and therapies involving biomaterials and therapeutic cells/organs. The intravascular innate immune system consists of the cascade systems of the blood (the complement, contact, coagulation, and fibrinolytic systems), the blood cells (polymorphonuclear cells, monocytes, platelets), and the endothelial cell lining of the vessels. Activation of the intravascular innate immune system in vivo leads to thromboinflammation that can be activated by several of the system's pathways and that initiates repair after tissue damage and leads to adverse reactions in several disorders and treatment modalities. In this review, we summarize the current knowledge in the field and discuss the obstacles that exist in order to study the cross-talk between the components of the intravascular innate immune system. These include the use of purified in vitro systems, animal models and various types of anticoagulants. In order to avoid some of these obstacles we have developed specialized human whole blood models that allow investigation of the cross-talk between the various cascade systems and the blood cells. We in particular stress that platelets are involved in these interactions and that the lectin pathway of the complement system is an emerging part of innate immunity that interacts with the contact/coagulation system. Understanding the resulting thromboinflammation will allow development of new therapeutic modalities.

  • 13.
    Teramura, Yuji
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Department of Bioengineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
    Asif, Sana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Nilsson Ekdahl, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Linnæus Center of Biomaterials Chemistry, Linnæus University, SE-391 82 Kalmar, Sweden.
    Gustafson, Elisabet K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Pediatric Surgery.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Cell Adhesion Induced Using Surface Modification with Cell-Penetrating Peptide-Conjugated Poly(ethylene glycol)-Lipid: A New Cell Glue for 3D Cell-Based Structures2017In: ACS Applied Materials and Interfaces, ISSN 1944-8244, E-ISSN 1944-8252, Vol. 9, no 1, p. 244-254Article in journal (Refereed)
    Abstract [en]

    We synthesized a novel material, cell-penetrating peptide-conjugated poly(ethylene glycol)-lipid (CPP-PEG-lipid), that can induce the adhesion of floating cells. Firm cell adhesion with spreading could be induced by cell surface modification with the CPP-PEG-lipids. Cell adhesion was induced by CPPs but not by any other cationic short peptides we tested. Here, we demonstrated adherence using the floating cell line CCRF-CEM as well as primary human T cells, B cells, erythrocytes, and hepatocytes. As compared to cells grown in suspension, adherent cells were more rapidly induced to attach to substrates with the cell-surface modification. The critical factor for attachment was localization of CPPs at the cell membrane by PEG-lipids with PEG > 20 kDa. These cationic CPPs on PEG chains were able to interact with substrate surfaces such as polystyrene (PS) surfaces, glass surfaces, and PS microfibers that are negatively charged, inducing firm cell adhesion and cell spreading. Also, as opposed to normal cationic peptides that interact strongly with cell membranes, CPPs were less interactive with the cell surfaces because of their cell-penetrating property, making them more available for adhering cells to the substrate surface. No effects on cell viability or cell proliferation were observed after the induction of cell adhesion. With this technique, cells could be easily immobilized onto PS microfibers, an important step in fabricating 3D cell-based structures. Cells immobilized onto 3D PS microfibers were alive, and human hepatocytes showed normal production of urea and albumin on the microfibers. This method is novel in inducing firm cell adhesion via a one-step treatment.

  • 14.
    Teramura, Yuji
    et al.
    Department of Bioengineering, The University of Tokyo, Bunkyo-ku, Japan.
    Asif, Sana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Nilsson Ekdahl, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Cell Surface Engineering for Regulation of Immune Reactions in Cell Therapy2015In: Advances in Experimental Medicine and Biology, ISSN 0065-2598, E-ISSN 2214-8019, Vol. 865, p. 189-209Article in journal (Refereed)
    Abstract [en]

    Transplantation of the pancreatic islets of Langerhans (islets) is a promising cell therapy for treating insulin-dependent type 1 diabetes mellitus. Islet transplantation is a minimally-invasive technique involving relatively simple surgery. However, after intraportal transplantation, the transplanted islets are attacked by the recipient's immune system, because they activate a number of systems, including coagulation, complement response, inflammation, immune rejection, and recurrence of autoimmune disease. We have developed a surface modification and microencapsulation technique that protects cells and islets with biomaterials and bioactive substances, which may be useful in clinical settings. This approach employs amphiphilic polymers, which can interact with lipid bilayer membranes, without increasing cell volume. Molecules attached to these polymers can protect transplanted cells and islets from attack by the host immune system. We expect that this surface modification technique will improve graft survival in clinical islet transplantation.

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