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  • 1.
    Basu, Alex
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Hong, Jaan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Ferraz, Natalia
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Hemocompatibility of Ca2+-Crosslinked Nanocellulose Hydrogels: Toward Efficient Management of Hemostasis2017In: Macromolecular Bioscience, ISSN 1616-5187, E-ISSN 1616-5195, 1-9 p., 1700236Article in journal (Refereed)
    Abstract [en]

    The present work investigates Ca2+-crosslinked nanofibrillated cellulose hydrogels as potential hemostatic wound dressings by studying core interactions between the materials and a central component of wounds and wound healing—the blood. Hydrogels of wood-derived anionic nanofibrillated cellulose (NFC) and NFC hydrogels that incorporate kaolin or collagen are studied in an in vitro whole blood model and with platelet-free plasma assays. The evaluation of thrombin and factor XIIa formation, platelet reduction, and the release of activated complement system proteins, shows that the NFC hydrogel efficiently triggered blood coagulation, with a rapid onset of clot formation, while displaying basal complement system activation. By using the NFC hydrogel as a carrier of kaolin, the onset of hemostasis is further boosted, while the NFC hydrogel containing collagen exhibits blood activating properties comparable to the anionic NFC hydrogel. The herein studied NFC hydrogels demonstrate great potential for being part of advanced wound healing dressings that can be tuned to target certain wounds (e.g., strongly hemorrhaging ones) or specific phases of the wound healing process for optimal wound management.

  • 2. Bexborn, Fredrik
    et al.
    Engberg, Anna E.
    Sandholm, Kerstin
    Mollnes, Tom Eirik
    Hong, Jaan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Nilsson Ekdahl, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Hirudin versus heparin for use in whole blood in vitro biocompatibility models2009In: Journal of Biomedical Materials Research. Part A, ISSN 1549-3296, Vol. 89A, no 4, 951-959 p.Article in journal (Refereed)
    Abstract [en]

    Heparin has traditionally been a widely used anticoagulant in blood research, but has been shown to be inappropriate for work with the complement system because of its complement-interacting properties. In this work, we have compared the effects of heparin with those of the specific thrombin inhibitor hirudin on complement and blood cells in vitro. Whole blood collected in the presence of hirudin (50 microg/mL) or heparin (1 IU/mL) was incubated in the slide chamber model. The plasma was analyzed for complement activation markers C3a and sC5b-9, and the polyvinylchloride test slides were stained for adhering cells. The integrity of the complement system was tested by incubating serum and hirudin-treated plasma in the presence of various activating agents. In contrast to heparin, the addition of hirudin generally preserved the complement reactivity, and complement activation in hirudin plasma closely resembled that in normal serum. Importantly, immunochemical staining of surface-bound cells demonstrated the inducible expression of tissue factor on bound monocytes from hirudin-treated blood, an effect that was completely abolished in heparin-treated blood. Our results indicate that hirudin as an anticoagulant produces more physiological conditions than heparin, making hirudin well-suited for in vitro studies, especially those addressing the regulation of cellular processes.

  • 3.
    Carlsson, Daniel O
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Ferraz, Natalia
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Hong, Jaan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Forensic Medicine.
    Nyholm, Leif
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Inorganic Chemistry.
    Strømme, Maria
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Mihranyan, Albert
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Conducting Nanocellulose Polypyrrole Membranes Intended for Hemodialysis2012In: European Cells and Materials, ISSN 1473-2262, E-ISSN 1473-2262, Vol. 23, no Suppl 5, 32-32 p.Article in journal (Refereed)
  • 4.
    Ek, Rebecca Klingvall
    et al.
    Mid Sweden Univ, Sports Tech Res Ctr, SE-83125 Ostersund, Sweden..
    Hong, Jaan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Thor, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Oral and Maxillofacial Surgery.
    Backstrom, Mikael
    Mid Sweden Univ, Sports Tech Res Ctr, SE-83125 Ostersund, Sweden..
    Rannar, Lars-Erik
    Mid Sweden Univ, Sports Tech Res Ctr, SE-83125 Ostersund, Sweden..
    Micro- to Macroroughness of Additively Manufactured Titanium Implants in Terms of Coagulation and Contact Activation2017In: International Journal of Oral & Maxillofacial Implants, ISSN 0882-2786, E-ISSN 1942-4434, Vol. 32, no 3, 565-574 p.Article in journal (Refereed)
    Abstract [en]

    Purpose: This study aimed to evaluate how as-built electron beam melting (EBM) surface properties affect the onset of blood coagulation. The properties of EBM-manufactured implant surfaces for placement have, until now, remained largely unexplored in literature. Implants with conventional designs and custom-made implants have been manufactured using EBM technology and later placed into the human body. Many of the conventional implants used today, such as dental implants, display modified surfaces to optimize bone ingrowth, whereas custom-made implants, by and large, have machined surfaces. However, titanium in itself demonstrates good material properties for the purpose of bone ingrowth. Materials and Methods: Specimens manufactured using EBM were selected according to their surface roughness and process parameters. EBM-produced specimens, conventional machined titanium surfaces, as well as PVC surfaces for control were evaluated using the slide chamber model. Results: A significant increase in activation was found, in all factors evaluated, between the machined samples and EBM-manufactured samples. The results show that EBM-manufactured implants with as-built surfaces augment the thrombogenic properties. Conclusion: EBM that uses Ti6Al4V powder appears to be a good manufacturing solution for load-bearing implants with bone anchorage. The as-built surfaces can be used "as is" for direct bone contact, although any surface treatment available for conventional implants can be performed on EBM-manufactured implants with a conventional design.

  • 5.
    Ekdahl, Kristina N.
    et al.
    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..
    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..
    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.
    Duehrkop, 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
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Paediatric 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 U.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Huber-Lang, Markus
    Univ Ulm, Dept Orthoped Trauma Hand Plast & Reconstruct Sur, Ulm, Germany..
    Garred, Peter
    Univ Copenhagen, Fac Hlth & Med Sci, Mol Med Lab, Rigshosp,Dept Clin Immunol,Sect 7631, 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, 245-269 p.Article, review/survey (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.

  • 6. Ekstrand-Hammarstrom, Barbro
    et al.
    Hong, Jaan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Davoodpour, Padideh
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Sandholm, Kerstin
    Ekdahl, Kristina N.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Bucht, Anders
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    TiO2 nanoparticles tested in a novel screening whole human blood model of toxicity trigger adverse activation of the kallikrein system at low concentrations2015In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 51, 58-68 p.Article in journal (Refereed)
    Abstract [en]

    There is a compelling need to understand and assess the toxicity of industrially produced nanoparticles (NPs). In order to appreciate the long-term effects of NPs, sensitive human-based screening tests that comprehensively map the NP properties are needed to detect possible toxic mechanisms. Animal models can only be used in a limited number of test applications and are subject to ethical concerns, and the interpretation of experiments in animals is also distorted by the species differences. Here, we present a novel easy-to-perform highly sensitive whole-blood model using fresh non-anticoagulated human blood, which most justly reflects complex biological cross talks in a human system. As a demonstrator of the tests versatility, we evaluated the toxicity of TiO2 NPs that are widely used in various applications and otherwise considered to have relatively low toxic properties. We show that TiO2 NPs at very low concentrations (50 ng/mL) induce strong activation of the contact system, which in this model elicits thromboinflammation. These data are in line with the finding of components of the contact system in the protein corona of the TiO2 NPs after exposure to blood. The contact system activation may lead to both thrombotic reactions and generation of bradykinin, thereby representing fuel for chronic inflammation in vivo and potentially long-term risk of autoimmunity, arteriosclerosis and cancer. These results support the notion that this novel whole-blood model represents an important contribution to testing of NP toxicity.

  • 7.
    Ferraz, Natalia
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Carlsson, Daniel O.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Hong, Jaan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Nyholm, Leif
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Inorganic Chemistry.
    Strømme, Maria
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Mihranyan, Albert
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Haemocompatibility and ion exchange capability of nanocellulose polypyrrole membranes intended for blood purification2012In: Journal of the Royal Society Interface, ISSN 1742-5689, E-ISSN 1742-5662, Vol. 9, no 73, 1943-1955 p.Article in journal (Refereed)
    Abstract [en]

    Composites of nanocellulose and the conductive polymer polypyrrole (PPy) are presented as candidates for a new generation of haemodialysis membranes. The composites may combine active ion exchange with passive ultrafiltration, and the large surface area (about 80 m2 g−1) could potentially provide compact dialysers. Herein, the haemocompatibility of the novel membranes and the feasibility of effectively removing small uraemic toxins by potential-controlled ion exchange were studied. The thrombogenic properties of the composites were improved by applying a stable heparin coating. In terms of platelet adhesion and thrombin generation, the composites were comparable with haemocompatible polymer polysulphone, and regarding complement activation, the composites were more biocompatible than commercially available membranes. It was possible to extract phosphate and oxalate ions from solutions with physiological pH and the same tonicity as that of the blood. The exchange capacity of the materials was found to be 600 ± 26 and 706 ± 31 μmol g−1 in a 0.1 M solution (pH 7.4) and in an isotonic solution of phosphate, respectively. The corresponding values with oxalate were 523 ± 5 in a 0.1 M solution (pH 7.4) and 610 ± 1 μmol g−1 in an isotonic solution. The heparinized PPy–cellulose composite is consequently a promising haemodialysis material, with respect to both potential-controlled extraction of small uraemic toxins and haemocompatibility.

  • 8.
    Ferraz, Natalia
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Carlsson, Daniel O
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Hong, Jaan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Nyholm, Leif
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Inorganic Chemistry.
    Strømme, Maria
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Mihranyan, Albert
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Hemocompatibility of Nanocellulose Polypyrrole Membranes Intended for Hemodialysis2012In: 9th World Biomaterials Congress, June 1-5, 2012, Chengdu, China, 2012Conference paper (Refereed)
  • 9.
    Ferraz, Natalia
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry, Surface Biotechnology.
    Hong, Jaan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Karlsson Ott, Marjam
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry, Surface Biotechnology.
    Procoagulant behavior and platelet microparticle generation on nanoporous alumina2010In: Journal of biomaterials applications, ISSN 0885-3282, E-ISSN 1530-8022, Vol. 24, no 8, 675-692 p.Article in journal (Refereed)
    Abstract [en]

    In the present work, we have investigated platelet microparticle(PMP) generation in whole blood after contact with nanoporous alumina.Alumina membranes with pore sizes of 20 and 200nm in diameter were incubated with whole blood and the number of PMP in the fluid phase was determined by flow cytometry. The role of the complement system in PMP generation was investigated using an analog of the potent complement inhibitor compstatin. Moreover, the procoagulant activity of the two pore size membranes were compared by measuring thrombin formation. Results indicated that PMP were not present in the fluid phase after whole blood contact with either of the alumina membranes. However, scanning electron microscope micrographs clearly showed the presence of PMP clusters on the 200nm pore size alumina, while PMP were practically absent on the 20nm membrane. We probed no influence of complement activation in PMP generation and adhesion and we hypothesize that other specific material-related protein–platelet interactions are taking place. A clear difference in procoagulant activity between the membranes could also be seen, 20nm alumina showed 100% higher procoagulant activity than 200nm membrane. By combining surface evaluation and flow cytometry analyses of the fluid phase, we are able to conclude that 200nm pore size alumina promotes PMP generation and adhesion while the 20nm membrane does not appreciably cause any release or adhesion of PMP, thus indicating a direct connection between PMP generation and nanoporosity.

  • 10.
    Ferraz, Natalia
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry, Surface Biotechnology.
    Hong, Jaan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Santin, Matteo
    School of Pharmacy & Biomolecualr Sciences, University of Brighton.
    Karlsson Ott, Marjam
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry, Surface Biotechnology.
    Nanoporosity of alumina surfaces induces different patterns of activation in adhering monocytes/macrophages2010In: International Journal of Biomaterials, ISSN 1687-8787, E-ISSN 1687-8795, Vol. 2010, 402715- p.Article in journal (Refereed)
    Abstract [en]

    The present study shows that alumina nanotopography affects monocyte/macrophage behaviour. Human mononuclear cells cultured on alumina membranes with pore diameters of 20 and 200 nm were evaluated in terms of cell adhesion, viability, morphology and release of pro-inflammatory cytokines. After 24 hours, cell adhesion was assessed by means of light microscopy and cell viability by measuring LDH release. The inflammatory response was evaluated by quantifying interleukin-1ß and tumour necrosis factor-α. Finally, scanning electron microscopy was used to study cell morphology. Results showed pronounced differences in cell number, morphology and cytokine release depending on the nanoporosity. Few but highly activated cells were found on the 200 nm porous alumina, while relatively larger number of cells was found on the 20 nm porous surface. However, despite their larger number, the cells adhering on the 20 nm surface exhibited reduced pro-inflammatory activity. It can be speculated that the difference in surface topography may lead to distinct protein adsorption patterns and therefore to different degree of cell activation. The data of this paper emphasize the role played by the material nanotexture in dictating cell responses and implies that nanotopography could be exploited for controlling the inflammatory response to implants.

  • 11.
    Ferraz, Natalia
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry, Surface Biotechnology.
    Karlsson Ott, Marjam
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry, Surface Biotechnology.
    Hong, Jaan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Time sequence of blood activation by nanoporous alumina: Studies on platelets and complement system2010In: Microscopy research and technique (Print), ISSN 1059-910X, E-ISSN 1097-0029, Vol. 73, no 12, 1101-1109 p.Article in journal (Refereed)
    Abstract [en]

    In the present work the time sequence of blood activation by alumina membranes with different porosities (20 and 200 nm in diameter) was studied. The membranes were incubated with whole blood from 2 min to 4 h. Platelet adhesion and activation in addition to complement activation were monitored at different time points. Evaluation of platelet adhesion and activation was done by determining the change in platelet number and the levels of thrombospondin-1 in the fluid phase. Scanning electron microscopy studies were done to further evaluate platelet adhesion and morphology. Immunocytochemical staining was used to evaluate the presence of CD41 and CD62P antigens on the material surface. Complement activation was monitored by measuring C3a and sC5b-9 in plasma samples by means of enzyme immunoassays. Both alumina membranes displayed similar complement activation time profiles, with levels of C3a and sC5b-9 increasing with incubation time. A statistically significant difference between the membranes was found after 60 min of incubation. Platelet activation characteristics and time profile were different between the two membranes. Platelet adhesion increased over time for the 20 nm surface, while the clusters of microparticles on the 200 nm surface did not appreciably change during the course of the experiment. The release of thrombospondin-1 increased with time for both membranes, however much later for the 200 nm alumina (240 min) as compared to the 20 nm membrane (60 min). The surface topography of the alumina most probably influence protein transition rate, which in turn affects material-platelet activation kinetics.

  • 12. Fink, Helen
    et al.
    Hong, Jaan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Drotz, Kristoffer
    Risberg, Bo
    Sanchez, Javier
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Selborn, Anders
    An in vitro study of blood compatibility of vascular grafts made of bacterial cellulose in comparison with conventionally-used graft materials2011In: Journal of Biomedical Materials Research - Part A, ISSN 1549-3296, Vol. 97A, no 1, 52-58 p.Article in journal (Refereed)
    Abstract [en]

    In this study we analyzed the blood compatibility of bacterial cellulose (BC) as a new biosynthetic material for use as a vascular graft. As reference materials we used expanded polytetrafluoroethylene (ePTFE) and poly(ethylene terephthalate) (PET) vascular grafts. These materials are in clinical use today. Tubes with inner diameters of both 4 (not PET) and 6 mm were tested. Heparin-coated PVC tubes (hepPVC) were used as a negative control. Platelet consumption and thrombin-antithrombin complex (TAT) were used as parameters of coagulation and for complement activation, sC3a and sC5b-9 were used. The investigated parameters were measured after 1-h exposure to freshly drawn human blood supplemented with a low dose of heparin in a Chandler loop system. The results showed that BC exhibits no significant difference in platelet consumption, as compared with PET 16 mm), ePTFE and hepPVC. The PET material consumed more platelets than any of the other materials. The TAT generation for 4 mm tubes was not significantly different between BC and the other materials. For 6 mm tubes, however, differences were observed between hepPVC and PET (p < 0.0001); BC and hepPVC (p = 0.0016); ePTFE and PET (p < 0.0001); BC and ePTFE (p = 0.0029); BC and PET (p = 0.0141). Surprisingly, considering the low platelet consumption, the complement activation parameters (sC3a and sC5b-9) were much higher for BC, as compared with the other materials for both 4 and 6 mm tubes.

  • 13.
    Frykstrand, Sara
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Forsgren, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Cheung, Ocean
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Zhang, Peng
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Hong, Jaan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Strømme, Maria
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Ferraz, Natalia
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Study of mesoporous magnesium carbonate in contact with whole human blood2016In: RSC Advances, ISSN 2046-2069, E-ISSN 2046-2069, Vol. 6, no 58, 52810-52816 p.Article in journal (Refereed)
    Abstract [en]

    The interaction of mesoporours magnesium carbonate (Upsalite) particles (50-100 mm) with human whole blood was investigated using an in vitro loop model and the effect on the complement system, blood coagulation and red blood cell lysis was assessed. The removal of Ca2+ by Upsalite and the possible exchange with and/or release of Mg2+ were explored as well. Upsalite was found to present anticoagulant properties, most probably due to the uptake of Ca2+ by the particles. No hemolytic activity was detected at Upsalite concentrations up to 1 mg ml(-1). Moderate to high levels of C3a and sC5b-9 were observed for Upsalite, however such levels were statistically different from the negative control only when the particle concentrations were 0.25 mg ml(-1) and 1.0 mg ml(-1), respectively. The presented findings are promising for the future development of mesoporous magnesium carbonate-based materials for biomedical applications.

  • 14.
    Hilborn, Jöns
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Materials Chemistry. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Materials Chemistry, Polymer Chemistry.
    Bowden, Tim
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Materials Chemistry. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Materials Chemistry, Polymer Chemistry.
    Nederberg, Fredrik
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Materials Chemistry. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Materials Chemistry, Polymer Chemistry.
    Hong, Jaan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Elvingson, Christer
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Materials Chemistry, Polymer Chemistry.
    Biodegradable phosphatidylcholine functional poly(e-caprolactone)2003In: PMSE Preprints (2003), 88, 2003, 109-110 p.Conference paper (Refereed)
  • 15.
    Hong, Jaan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Andersson, Joakim
    Nilsson Ekdahl, K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Elgue, Graciela
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Axen, N
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Titanium is a highly thrombogenic biomaterial: Possible implications for osteogenesis1999In: Thromb Haem, Vol. 82, 58- p.Article in journal (Refereed)
  • 16.
    Hong, Jaan
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Teknisk-naturvetenskapliga vetenskapsområdet, Technology, Department of Engineering Sciences, Solid State Physics. Klinisk immunologi.
    Azens, Andris
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Technology, Department of Engineering Sciences. Teknisk-naturvetenskapliga vetenskapsområdet, Technology, Department of Engineering Sciences, Solid State Physics.
    Nilsson Ekdahl, Kristina
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Teknisk-naturvetenskapliga vetenskapsområdet, Technology, Department of Engineering Sciences, Solid State Physics. Klinisk immunologi.
    Granqvist, Claes Göran
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Technology, Department of Engineering Sciences. Teknisk-naturvetenskapliga vetenskapsområdet, Technology, Department of Engineering Sciences, Solid State Physics.
    Nilsson, Bo
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Teknisk-naturvetenskapliga vetenskapsområdet, Technology, Department of Engineering Sciences, Solid State Physics. Klinisk immunologi.
    Material-specific thrombin generation following contact between metal surfaces and whole blood.2005In: Biomaterials, ISSN 0142-9612, Vol. 26, no 12, 1397-403 p.Article in journal (Refereed)
  • 17.
    Hong, Jaan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Kurt, Seta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Thor, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Oral and Maxillofacial Surgery.
    A Hydrophilic Dental Implant Surface Exhibit Thrombogenic Properties In Vitro2013In: Clinical Implant Dentistry and Related Research, ISSN 1523-0899, E-ISSN 1708-8208, Vol. 15, no 1, 105-112 p.Article in journal (Refereed)
    Abstract [en]

    Background:

    Surface modifications of dental implants have gained attention during several years and the thrombotic response from blood components with these materials has become more important during recent years.

    Purpose:

    The aims of this study were to evaluate the thrombogenic response of whole blood, in contact with clinically used dental surfaces, Sandblasted Large grit Acid etched titanium (SLA) and Sandblasted Large grit Acid etched, and chemically modified titanium with hydrophilic properties (SLActive).

    Methods:

    An in vitro slide chamber model, furnished with heparin, was used in which whole blood came in contact with slides of the test surfaces. After incubation (60-minute rotation at 22 rpm in a 37°C water bath), blood was mixed with ethylenediaminetetraacetic acid (EDTA) or citrate, further centrifuged at +4°C. Finally, plasma was collected pending analysis.

    Results:

    Whole blood in contact with surfaces resulted in significantly higher binding of platelets to the hydrophilic surface, accompanied by a significant increase of contact activation of the coagulation cascade. In addition, the platelet activation showed a similar pattern with a significant elevated release of β-TG from platelet granule.

    Conclusions:

    The conclusion that can be drawn from the results in our study is that the hydrophilic modification seems to augment the thrombogenic properties of titanium with implications for healing into bone of, that is titanium dental implants.

  • 18.
    Hong, Jaan
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Larsson, Anders
    Department of Medical Sciences.
    Ekdahl, Kristina
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Elgue, Graciela
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Larsson, Rolf
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Nilsson, Bo
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Contact between a polymer and whole blood: sequence of events leading to thrombin generation.2001In: J Lab Clin Med, Vol. 138, 139- p.Article in journal (Refereed)
  • 19.
    Hong, Jaan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology and Transfusion Medicine. Klinisk immunologi.
    Nilsson Ekdahl, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology and Transfusion Medicine.
    Reynolds, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology and Transfusion Medicine.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology and Transfusion Medicine.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology and Transfusion Medicine.
    A new in vitro model to study interaction between whole blood and biomaterials. Studies of platelet and coagulation activation and the effect of aspirin1999In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 20, no 7, 603-611 p.Article in journal (Refereed)
    Abstract [en]

    We have developed a versatile in vitro chamber model with a double purpose: first, to be able to study mechanisms of bio- incompatibility, and, second, to test biomaterials at all levels of interactions, in whole blood. The use of biomaterials in the form of microscope slides as walls in the chamber makes it possible to analyse both the biomaterial surface with regard to protein and cell binding, as well as the molecular events taking place in the fluid. Incubation of blood in the chamber, for 60 min at 37°C resulted in the rapid binding of complement and coagulation proteins and of leukocytes and platelets to polyvinylchloride (PVC) slides. The cells formed a layer which more or less covered the underlying surface. Unlike complement activation, as reflected by soluble C3a and C5b-9, the thrombin—antithrombin formation was completely nullified in cell-depleted plasma. Despite the fact that throm- bin—antithrombin generation was also negligible in platelet-rich plasma, inhibition of platelet aggregation on the material surface with aspirin resulted in suppressed generation of thrombin—antithrombin complexes. Taken together, the coagulation activation in the chamber was dependent on the presence of blood cells which suggests that bound/aggregated platelets initiate a sequence of events involving leukocytes that results in coagulation activation. 

  • 20.
    Hårdstedt, Maria
    et al.
    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, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Center for Clinical Research Dalarna.
    Lindblom, Susanne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Hong, Jaan
    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.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Ronquist, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    A novel model for studies of blood-mediated long-term responses to cellular transplants2015In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 120, no 1, 28-39 p.Article in journal (Refereed)
    Abstract [en]

    Aims

    Interaction between blood and bio-surfaces is important in many medical fields. With the aim of studying blood-mediated reactions to cellular transplants, we developed a whole-blood model for incubation of small volumes for up to 48 h.

    Methods

    Heparinized polyvinyl chloride tubing was cut in suitable lengths and sealed to create small bags. Multiple bags, with fresh venous blood, were incubated attached to a rotating wheel at 37°C. Physiological variables in blood were monitored: glucose, blood gases, mono- and divalent cations and chloride ions, osmolality, coagulation (platelet consumption, thrombin-antithrombin complexes (TAT)), and complement activation (C3a and SC5b-9), haemolysis, and leukocyte viability.

    Results

    Basic glucose consumption was high. Glucose depletion resulted in successive elevation of extracellular potassium, while sodium and calcium ions decreased due to inhibition of energy-requiring ion pumps. Addition of glucose improved ion balance but led to metabolic acidosis. To maintain a balanced physiological environment beyond 6 h, glucose and sodium hydrogen carbonate were added regularly based on analyses of glucose, pH, ions, and osmotic pressure. With these additives haemolysis was prevented for up to 72 h and leukocyte viability better preserved. Despite using non-heparinized blood, coagulation and complement activation were lower during long-term incubations compared with addition of thromboplastin and collagen.

    Conclusion

    A novel whole-blood model for studies of blood-mediated responses to a cellular transplant is presented allowing extended observations for up to 48 h and highlights the importance of stringent evaluations and adjustment of physiological conditions.

  • 21. Nederberg, Fredrik
    et al.
    Bowden, Tim
    Nilsson, Bo
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. KITM.
    Hong, Jaan
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. KITM.
    Hilborn, Jöns
    Phosphoryl choline introduces dual activity in biomimetic ionomers.2004In: J Am Chem Soc, ISSN 0002-7863, Vol. 126, no 47, 15350-1 p.Article in journal (Refereed)
  • 22.
    Nederberg, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Materials Chemistry.
    Bowden, Tim
    Nilsson, Bo
    Hong, Jaan
    Hilborn, Jöns
    Phosphoryl choline introduces dual activity in biomimetic ionomers2004In: Journal of the American Chemical Society, ISSN 0002-7863, Vol. 126, no 47, 15350-15351 p.Article in journal (Refereed)
  • 23.
    Nederberg, Fredrik
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Materials Chemistry. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Materials Chemistry, Polymer Chemistry. polymerkemi.
    Bowden, Tim
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Materials Chemistry. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Materials Chemistry, Polymer Chemistry. polymerkemi.
    Nilsson, Bo
    Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Materials Chemistry, Polymer Chemistry.
    Hong, Jaan
    Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Materials Chemistry, Polymer Chemistry.
    Hilborn, Jöns
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Materials Chemistry. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Materials Chemistry, Polymer Chemistry. polymerkemi.
    Phosphoryl Choline Introduces Dual Activity in Biomimetic Ionomers2004In: Journal of the American Chemical Society, no 126, 15350-15351 p.Article in journal (Refereed)
    Abstract [en]

    Dual activity of phosphoryl choline (PC) functional poly(trimethylene

    carbonate) (PTMC) was found which induces the zwitterionic biomimetic PC group to form physical cross-links with ionomers in the bulk, and at the same time enrich at the surface of cast films. The formation of zwitterionic domains from a bifunctional PC-PTMC-PC (ionomer) provided firm films with a low elastic modulus in contrast to the tacky PTMC starting material (Mn 3900 g/mol) with poor mechanical performance. In addition, the ionomer possessed improved hemocompatible properties that was explained by the enrichment of PC at the surface, suggesting a way to tailor the mechanical performance of biodegradable PTMC-based ionomers while providing its bioactivity. Tailored elasticity while maintaining hemocompatibility of a biodegradable ionomer should be of particular interest for a variety of in vivo applications.

  • 24.
    Nilsson Ekdahl, Kristina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Hong, Jaan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Hamad, Osama
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Larsson, Rolf
    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.
    Evaluation of the blood compatibility of materials, cells and tissues: Basic concepts, test models and practical guidelines2013In: Advances in Experimental Medicine and Biology, ISSN 0065-2598, E-ISSN 2214-8019, Vol. 735, 257-270 p.Article in journal (Refereed)
    Abstract [en]

    Medicine today uses a wide range of biomaterials, most of which make contact with blood permanently or transiently upon implantation. Contact between blood and nonbiological materials or cells or tissue of nonhematologic origin initiates activation of the cascade systems (complement, contact activation/coagulation) of the blood, which induces platelet and leukocyte activation.

    Although substantial progress regarding biocompatibility has been made, many materials and medical treatment procedures are still associated with severe side effects. Therefore, there is a great need for adequate models and guidelines for evaluating the blood compatibility of biomaterials. Due to the substantial amount of cross talk between the different cascade systems and cell populations in the blood, it is advisable to use an intact system for evaluation.

    Here, we describe three such in vitro models for the evaluation of the biocompatibility of materials and therapeutic cells and tissues. The use of different anticoagulants and specific inhibitors in order to be able to dissect interactions between the different cascade systems and cells of the blood is discussed. In addition, we describe two clinically relevant medical treatment modalities, the integration of titanium implants and transplantation of islets of Langerhans to patients with type 1 diabetes, whose mechanisms of action we have addressed using these in vitro models.

  • 25. Nilsson, Per H.
    et al.
    N. Ekdahl, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Magnusson, Peetra U.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Qu, Hongchang
    Iwata, Hiroo
    Ricklin, Daniel
    Hong, Jaan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Lambris, John D.
    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.
    Autoregulation of thromboinflammation on biomaterial surfaces by a multicomponent therapeutic coating2013In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 34, no 4, 985-994 p.Article in journal (Refereed)
    Abstract [en]

    Activation of the thrombotic and complement systems is the main recognition and effector mechanisms in the multiple adverse biological responses triggered when biomaterials or therapeutic cells come into blood contact. We have created a surface which is auto-protective to human innate immunity by combining three fundamentally different strategies, all developed by us previously, which have been shown to induce substantial, but incomplete hemocompatibility when used separately. In summary, we have conjugated a factor H-binding peptide; and an ADP-degrading enzyme; using a PEG linker on both material and cellular surfaces. When exposed to human whole blood, factor H was specifically recruited to the modified surfaces and inhibited complement attack. In addition, activation of platelets and coagulation was efficiently attenuated, by degrading ADP. Thus, by inhibiting thromboinflammation using a multicomponent approach, we have created a hybrid surface with the potential to greatly reduce incompatibility reactions involving biomaterials and transplantation.

  • 26.
    Nordling, Sofia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Hong, Jaan
    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.
    Edin, Fredrik
    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 Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Brännström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Magnusson, Peetra U.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Vascular repair utilising immobilised heparin conjugate for protection against early activation of inflammation and coagulation2015In: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 113, no 6, 1312-1322 p.Article in journal (Refereed)
    Abstract [en]

    Ischaemia-reperfusion injury (IRI) poses a major challenge in many thrombotic conditions and in whole organ transplantation. Activation of the endothelial cells and shedding of the protective vascular glycocalyx during IRI increase the risk of innate immune activation, cell infiltration and severe thrombus formation, promoting damage to the tissue. Here, we present a novel one-step strategy to protect the vas, culature by immobilisation of a unique multi-arm heparin conjugate to the endothelium. Applying a new in vitro blood endothelial cell chamber model, the heparin conjugate was found to bind not only to primary human endothelial cells but also directly to the collagen to which the cells adhered. Incubation of hypoxic endothelial cells with freshly drawn human blood in the blood chambers elicited coagulation activation reflected by thrombin anti-thrombin formation and binding of platelets and neutrophils. Immobilisation of the heparin conjugate to the hypoxic endothelial cells created a protective coating, leading to a Significant reduction of the recruitment of blood cells and coagulation activation compared to untreated hypoxic endothelial cells. This novel approach of immobilising multi-arm heparin conjugates on the endothelial cells and collagen of the basement membrane ensures to protect the endothelium against IRI in thrombotic disorders and in transplantation.

  • 27.
    Teramura, Yuji
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Nilsson, Per H.
    Ekdahl, Kristina N.
    Magnusson, Peetra U.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Qu, Hongchang
    Ricklin, Daniel
    Hong, Jaan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Lambris, John D.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Autoregulation of thromboinflammation on biomaterials and cells by a novel therapeutic coating technique2012In: Immunobiology, ISSN 0171-2985, E-ISSN 1878-3279, Vol. 217, no 11, 1140-1140 p.Article in journal (Other academic)
  • 28.
    Thor, Andreas Li
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Oral and Maxillofacial Surgery.
    Hong, Jaan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Kjeller, Göran
    Sennerby, Lars
    Rasmusson, Lars
    Correlation of Platelet Growth Factor Release in Jawbone Defect Repair: A Study in the Dog Mandible2013In: Clinical Implant Dentistry and Related Research, ISSN 1523-0899, E-ISSN 1708-8208, Vol. 15, no 5, 759-768 p.Article in journal (Refereed)
    Abstract [en]

    Background:

    Platelet concentrate/platelet-rich plasma (PRP) has been studied extensively in various experimental models and there is some agreement among workers to its early effect in bone regeneration and healing. We have earlier showed in vitro that titanium in whole blood activates the thrombogenic response to a higher degree than PRP and that a fluoridated test surface augmented the effect compared with control.

    Purpose:

    We designed this study to evaluate the effect of PRP and whole blood on bone regeneration in a dog implant defect model and, in addition, the effect of a test surface modified in hydrofluoric acid. A correlation attempt between platelet count, release of growth factors, and bone regeneration was made.

    Materials and Methods:

    Six dogs were used and simultaneously with the experimental surgery and implant installation, autologous PRP was prepared. Defects were prepared (6 mm in diameter and 5 mm deep), and implants were installed (TiO2 gritblasted and hydrofluoric acid treated [test] or TiO2 gritblasted [control], 5 mm in diameter and 9 mm long) in defects filled with either PRP or whole blood. Randomization of sides between PRP and whole blood, and sites for test and control implants were made. Blood samples were collected from PRP and whole blood. The dogs were killed after 5 weeks of healing, and samples with implants and surrounding bone were collected and processed for analysis. Enzyme linked immunosorbent assays were used for detection of growth factors in PRP.

    Results:

    The mean increase of platelet count was 424% in PRP. A correlation for platelet counts and transforming growth factor β was found in each dog (r2 = 0.857). Approximately 50% of the region of interest (ROI) in the defects was filled with new bone after 5 weeks. No difference could be observed in ROI by using PRP or whole blood in the defects regarding new bone formation, bone in contact with implant, or distance to first bone contact. However, the fluoridated implants exhibited more new bone formation (p = .03) compared with control, regardless of comparing PRP or whole blood, and also displayed a shorter distance from first bone contact to the margin of the bone envelope (p = .05).

    Conclusions:

    Platelet concentrate/PRP failed to show more new bone regeneration in a peri-implant defect model compared with whole blood. Implants treated with hydrofluoric acid displayed higher percentages of bone fill in the defect.

  • 29.
    Thor, Andreas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Oral and Maxillofacial Surgery.
    Rasmusson, Lars
    Biomaterialvetenskap Göteborgs universitet.
    Wennerberg, Ann
    Biomaterialvetenskap Göteborgs universitet.
    Thomsen, Peter
    Biomaterialvetenskap Göteborgs universitet.
    Hirsch, Jan-Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Oral and Maxillofacial Surgery.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Hong, Jaan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    The role of whole blood in thrombin generation in contact with various titanium surfaces2007In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 28, no 6, 966-974 p.Article in journal (Refereed)
    Abstract [en]

    Understanding of the thrombotic response (activation of the intrinsic coagulation system followed by platelet activation) from blood components upon contact with a titanium dental implant is important and not fully understood. The aims of this study were to evaluate: (1) the thrombogenic response of whole blood, platelet-rich plasma (PRP) and platelet-poor plasma (PPP) in contact with a highly thrombogenic surface as titanium, (2) the thrombogenic response of clinically used surfaces as hydroxyapatite (HA), machined titanium (mTi), TiO2 grit-blasted titanium (TiOB) and fluoride ion-modified grit-blasted titanium (TiOB-F). An in vitro slide chamber model, furnished with heparin, was used in which whole blood, PRP or PPP came in contact with slides of the test surfaces. After incubation (60 min rotation at 22 rpm in a 37 degrees C water bath), blood/plasma was mixed with EDTA or citrate, further centrifuged at +4 degrees C (2200 g at 10 min). Finally, plasma was collected pending analysis. Whole blood in contact with Ti alloy resulted in the binding of platelets to the material surface and in the generation of thrombin-antithrombin (TAT) complexes. With whole blood TAT levels increased 1000-fold compared with PRP and PPP, in which both almost no increase of TAT could be detected. In addition, the platelet activation showed a similar pattern with a 15-fold higher release of beta-TG in whole blood. In the in vitro chamber model with the clinically relevant materials, the fluoride-modified surface (TiOB-F) showed pronounced TAT generation compared with TiOB, mTi and HA. Similar results were achieved for platelet consumption and activation markers of the intrinsic coagulation system. Taken together these results implicate first that whole blood is necessary for sufficient thrombin generation and platelet activation during placement of implants. Second, a fluoride ion modification seems to augment the thrombogenic properties of titanium.

1 - 29 of 29
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