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  • 1. Mladenović, Živko
    et al.
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Odontology.
    Willman, Britta
    Umeå University, Faculty of Medicine, Department of Odontology.
    Shahabi, Kaveh
    Umeå University, Faculty of Medicine, Department of Odontology.
    Björn, Erik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Ransjö, Maria
    Soluble silica inhibits osteoclast formation and bone resorption in vitro2014In: Acta Biomaterialia, ISSN 1742-7061, E-ISSN 1878-7568, Vol. 10, no 1, p. 406-418Article in journal (Refereed)
    Abstract [en]

    Several studies have suggested that silicon (Si) may be essential for normal development of connective tissue and the skeleton. Positive effects of Si from the diet as well as from Si-containing biomaterials, such as Bioactive glass 45S5 (BG), have been demonstrated. Studies have reported that Si stimulates osteoblast proliferation and differentiation. However, effects of Si on osteoclasts have not been directly addressed earlier. The purpose of the present in vitro study was to clarify if Si has regulatory effects on osteoclasts formation and bone resorption. Effects of BG, BG dissolution extracts and Si containing cell culture medium were investigated in a mouse calvarial bone resorption assay and osteoclast formation assays (mouse bone marrow cultures and RAW264.7 cell cultures). We conclude from our results that Si causes significant inhibition of osteoclast phenotypic gene expressions, osteoclast formation and bone resorption in vitro. In conclusion, the present study suggests that Si has a dual nature in bone metabolism with stimulatory effects on osteoblasts and inhibitory effects on osteoclasts. This suggested property of Si might be interesting to further explore in future biomaterials for treatments of bone defects in patients.

  • 2.
    Novikova, Liudmila N.
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Kolar, Mallappa K.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Kingham, Paul J.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Ullrich, Andreas
    Oberhoffner, Sven
    Renardy, Monika
    Doser, Michael
    Müller, Erhard
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Novikov, Lev N.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Trimethylene carbonate-caprolactone conduit with poly-p-dioxanone microfilaments to promote regeneration after spinal cord injury2018In: Acta Biomaterialia, ISSN 1742-7061, E-ISSN 1878-7568, Vol. 66, p. 177-191Article in journal (Refereed)
    Abstract [en]

    Spinal cord injury (SCI) is often associated with scarring and cavity formation and therefore bridging strategies are essential to provide a physical substrate for axonal regeneration. In this study we investigated the effects of a biodegradable conduit made from trimethylene carbonate and c-caprolactone (TC) containing poly-p-dioxanone microfilaments (PDO) with longitudinal grooves on regeneration after SCI in adult rats. In vitro studies demonstrated that different cell types including astrocytes, meningeal fibroblasts, Schwann cells and adult sensory dorsal root ganglia neurons can grow on the TC and PDO material. For in vivo experiments, the TC/PDO conduit was implanted into a small 2-3 mm long cavity in the C3-C4 cervical segments immediately after injury (acute SCI) or at 2-5 months after initial surgery (chronic SCI). At 8 weeks after implantation into acute SCI, numerous 5HT-positive descending raphaespinal axons and sensory CGRP-positive axons regenerated across the conduit and were often associated with PDO microfilaments and migrated host cells. Implantation into chronically injured SCI induced regeneration mainly of the sensory CGRP-positive axons. Although the conduit had no effect on the density of OX42-positive microglial cells when compared with SCI control, the activity of GFAP-positive astrocytes was reduced. The results suggest that a TC/PDO conduit can support axonal regeneration after acute and chronic SCI even without addition of exogenous glial or stem cells.

  • 3.
    Rzhepishevska, Olena I.
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Limanska, Nataliia
    Galkin, Mykola
    Lacoma, Alicia
    Lundquist, Margaretha
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Sokol, Dmytro
    Hakobyan, Shoghik
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Queen Mary University of London, London, UK.
    Sjöstedt, Anders
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Prat, Cristina
    Ramstedt, Madeleine
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Characterization of clinically relevant model bacterial strains of Pseudomonas aeruginosa for anti-biofilm testing of materials2018In: Acta Biomaterialia, ISSN 1742-7061, E-ISSN 1878-7568, Vol. 76, p. 99-107Article in journal (Refereed)
    Abstract [en]

    There is a great interest in developing novel anti-biofilm materials in order to decrease medical device-associated bacterial infections causing morbidity and high healthcare costs. However, the testing of novel materials is often done using bacterial lab strains that may not exhibit the same phenotype as clinically relevant strains infecting medical devices. Furthermore, no consensus of strain selection exists in the field, making results very difficult to compare between studies. In this work, 19 clinical isolates of Pseudomonas aeruginosa originating from intubated patients in an intensive care unit have been characterized and compared to the lab reference strain PAO1 and a rmlC lipopolysaccharide mutant of PAO1. The adhesion and biofilm formation was monitored, as well as cell properties such as hydrophobicity, zeta potential and motility. Two groups of isolates were observed: one with high adhesion to polymer surfaces and one with low adhesion (the latter including PAO1). Furthermore, detailed biofilm assays in a flow system were performed using five characteristic isolates from the two groups. Confocal microscopy showed that the adhesion and biofilm formation of four of these five strains could be reduced dramatically on zwitterionic surface coatings. However, one isolate with pronounced swarming colonized and formed biofilm also on the antifouling surface. We demonstrate that the biofilm properties of clinical isolates can differ greatly from that of a standard lab strain and propose two clinical model strains for testing of materials designed for prevention of biofilm formation in the respiratory tract. The methodology used could beneficially be applied for screening of other collections of pathogens to identify suitable model strains for in vitro biofilm testing.

    Statement of Significance: Medical-device associated infections present a great challenge in health care. Therefore, much research is undertaken to prevent bacterial colonization of new types of biomaterials. The work described here characterizes, tests and presents a number of clinically relevant bacterial model strains for assessing biofilm formation by Pseudomonas aeruginosa. Such model strains are of importance as they may provide better predictability of lab testing protocols with respect to how well materials would perform in an infection situation in a patient. Furthermore, this study uses the strains to test the performance of polymer surfaces designed to repel bacterial adhesion and it is shown that the biofilm formation for four out of the five tested bacterial strains was reduced.

    The full text will be freely available from 2020-06-12 00:00
  • 4. Sjollema, Jelmer
    et al.
    Zaat, Sebastian A.J.
    Fontaine, Veronique
    Ramstedt, Madeleine
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Luginbuehl, Reto
    Thevissen, Karin
    Li, Jiuyi
    van der Mei, Henny C.
    Busscher, Henk J.
    In vitro methods for the evaluation of antimicrobial surface designs2018In: Acta Biomaterialia, ISSN 1742-7061, E-ISSN 1878-7568, Vol. 70, p. 12-24Article in journal (Refereed)
    Abstract [en]

    Bacterial adhesion and subsequent biofilm formation on biomedical implants and devices are a major cause of their failure. As systemic antibiotic treatment is often ineffective, there is an urgent need for antimicrobial biomaterials and coatings. The term “antimicrobial” can encompass different mechanisms of action (here termed “antimicrobial surface designs”), such as antimicrobial-releasing, contact-killing or non-adhesivity. Biomaterials equipped with antimicrobial surface designs based on different mechanisms of action require different in vitro evaluation methods. Available industrial standard evaluation tests do not address the specific mechanisms of different antimicrobial surface designs and have therefore been modified over the past years, adding to the myriad of methods available in the literature to evaluate antimicrobial surface designs. The aim of this review is to categorize fourteen presently available methods including industrial standard tests for the in vitro evaluation of antimicrobial surface designs according to their suitability with respect to their antimicrobial mechanism of action. There is no single method or industrial test that allows to distinguish antimicrobial designs according to all three mechanisms identified here. However, critical consideration of each method clearly relates the different methods to a specific mechanism of antimicrobial action. It is anticipated that use of the provided table with the fourteen methods will avoid the use of wrong methods for evaluating new antimicrobial designs and therewith facilitate translation of novel antimicrobial biomaterials and coatings to clinical use. The need for more and better updated industrial standard tests is emphasized. Statement of Significance European COST-action TD1305, IPROMEDAI aims to provide better understanding of mechanisms of antimicrobial surface designs of biomaterial implants and devices. Current industrial evaluation standard tests do not sufficiently account for different, advanced antimicrobial surface designs, yet are urgently needed to obtain convincing in vitro data for approval of animal experiments and clinical trials. This review aims to provide an innovative and clear guide to choose appropriate evaluation methods for three distinctly different mechanisms of antimicrobial design: (1) antimicrobial-releasing, (2) contact-killing and (3) non-adhesivity. Use of antimicrobial evaluation methods and definition of industrial standard tests, tailored toward the antimicrobial mechanism of the design, as identified here, fulfill a missing link in the translation of novel antimicrobial surface designs to clinical use.

  • 5. Thomson, Suzanne E.
    et al.
    Charalambous, Chloe
    Smith, Carol-Anne
    Tsimbouri, Penelope M.
    Déjardin, Theophile
    Kingham, Paul J.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Hart, Andrew M.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). The Centre for Cell Engineering, College of Medical, Veterinary and Life Sciences, University of Glasgow, University Avenue, Hillhead, Glasgow G128QQ, UK; Canniesburn Plastic Surgery Unit, Glasgow Royal Infirmary, 84 Castle Street, Glasgow G4 0SF, UK.
    Riehle, Mathis O.
    Microtopographical cues promote peripheral nerve regeneration via transient mTORC2 activation2017In: Acta Biomaterialia, ISSN 1742-7061, E-ISSN 1878-7568, Vol. 60, p. 220-231Article in journal (Refereed)
    Abstract [en]

    Despite microsurgical repair, recovery of function following peripheral nerve injury is slow and often incomplete. Outcomes could be improved by an increased understanding of the molecular biology of regeneration and by translation of experimental bioengineering strategies. Topographical cues have been shown to be powerful regulators of the rate and directionality of neurite regeneration, and in this study we investigated the downstream molecular effects of linear micropatterned structures in an organotypic explant model. Linear topographical cues enhanced neurite outgrowth and our results demonstrated that the mTOR pathway is important in regulating these responses. mTOR gene expression peaked between 48 and 72 h, coincident with the onset of rapid neurite outgrowth and glial migration, and correlated with neurite length at 48 h. mTOR protein was located to glia and in a punctate distribution along neurites. mTOR levels peaked at 72 h and were significantly increased by patterned topography (p < 0.05). Furthermore, the topographical cues could override pharmacological inhibition. Downstream phosphorylation assays and inhibition of mTORC1 using rapamycin highlighted mTORC2 as an important mediator, and more specific therapeutic target. Quantitative immunohistochemistry confirmed the presence of the mTORC2 component rictor at the regenerating front where it co-localised with F-actin and vinculin. Collectively, these results provide a deeper understanding of the mechanism of action of topography on neural regeneration, and support the incorporation of topographical patterning in combination with pharmacological mTORC2 potentiation within biomaterial constructs used to repair peripheral nerves.

    Statement of Significance: Peripheral nerve injury is common and functionally devastating. Despite microsurgical repair, healing is slow and incomplete, with lasting functional deficit. There is a clear need to translate bioengineering approaches and increase our knowledge of the molecular processes controlling nerve regeneration to improve the rate and success of healing. Topographical cues are powerful determinants of neurite outgrowth and represent a highly translatable engineering strategy. Here we demonstrate, for the first time, that microtopography potentiates neurite outgrowth via the mTOR pathway, with the mTORC2 subtype being of particular importance. These results give further evidence for the incorporation of microtopographical cues into peripheral nerve regeneration conduits and indicate that mTORC2 may be a suitable therapeutic target to potentiate nerve regeneration.

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