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  • 1. Blau, Axel
    et al.
    Murr, Angelika
    Wolff, Sandra
    Sernagor, Evelyne
    Medini, Paolo
    Iurilli, Giuliano
    Ziegler, Christiane
    Benfenati, Fabio
    Flexible, all-polymer microelectrode arrays for the capture of cardiac and neuronal signals2011In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 32, no 7, p. 1778-1786Article in journal (Refereed)
    Abstract [en]

    Microelectrode electrophysiology has become a widespread technique for the extracellular recording of bioelectrical signals. To date, electrodes are made of metals or inorganic semiconductors, or hybrids thereof. We demonstrate that these traditional conductors can be completely substituted by highly flexible electroconductive polymers. Pursuing a two-level replica-forming strategy, conductive areas for electrodes, leads and contact pads are defined as microchannels in poly(dimethylsiloxane) (PDMS) as a plastic carrier and track insulation material. These channels are coated by films of organic conductors such as polystyrenesulfonate-doped poly(3,4-ethylenedioxy-thiophene) (PEDOT:PSS) or filled with a graphite-PDMS (gPDMS) composite, either alone or in combination. The bendable, somewhat stretchable, non-cytotoxic and biostable all-polymer microelectrode arrays (polyMEAs) with a thickness below 500 μm and up to 60 electrodes reliably capture action potentials (APs) and local field potentials (LFPs) from acute preparations of heart muscle cells and retinal whole mounts, in vivo epicortical and epidural recordings as well as during long-term in vitro recordings from cortico-hippocampal co-cultures.

  • 2. Ekstrand-Hammarström, Barbro
    et al.
    Hong, Jaan
    Davoodpour, Padideh
    Sandholm, Kerstin
    Ekdahl, Kristina N.
    Bucht, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Nilsson, Bo
    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, p. 58-68Article 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. 

  • 3. Georgiou, Melanie
    et al.
    Golding, Jon P.
    Loughlin, Alison J.
    Kingham, Paul J.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Phillips, James B.
    Engineered neural tissue with aligned, differentiated adipose-derived stem cells promotes peripheral nerve regeneration across a critical sized defect in rat sciatic nerve2015In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 37, p. 242-251Article in journal (Refereed)
    Abstract [en]

    Adipose-derived stem cells were isolated from rats and differentiated to a Schwann cell-like phenotype in vitro. The differentiated cells (dADSCs) underwent self-alignment in a tethered type-1 collagen gel, followed by stabilisation to generate engineered neural tissue (EngNT-dADSC). The pro-regenerative phenotype of dADSCs was enhanced by this process, and the columns of aligned dADSCs in the aligned collagen matrix supported and guided neurite extension in vitro. EngNT-dADSC sheets were rolled to form peripheral nerve repair constructs that were implanted within NeuraWrap conduits to bridge a 15 mm gap in rat sciatic nerve. After 8 weeks regeneration was assessed using immunofluorescence imaging and transmission electron microscopy and compared to empty conduit and nerve graft controls. The proportion of axons detected in the distal stump was 3.5 fold greater in constructs containing EngNT-dADSC than empty tube controls. Our novel combination of technologies that can organise autologous therapeutic cells-within an artificial tissue construct provides a promising new cellular biomaterial for peripheral nerve repair. 

  • 4. Labenski, Verena
    et al.
    Suerth, Julia D
    Barczak, Elke
    Heckl, Dirk
    Levy, Camille
    Bernadin, Ornellie
    Charpentier, Emmanuelle
    Department of Regulation in Infection Biology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
    Williams, David A
    Fehse, Boris
    Verhoeyen, Els
    Schambach, Axel
    Alpharetroviral self-inactivating vectors produced by a superinfection-resistant stable packaging cell line allow genetic modification of primary human T lymphocytes.2016In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 97, p. 97-109Article in journal (Refereed)
    Abstract [en]

    Primary human T lymphocytes represent an important cell population for adoptive immunotherapies, including chimeric-antigen and T-cell receptor applications, as they have the capability to eliminate non-self, virus-infected and tumor cells. Given the increasing numbers of clinical immunotherapy applications, the development of an optimal vector platform for genetic T lymphocyte engineering, which allows cost-effective high-quality vector productions, remains a critical goal. Alpharetroviral self-inactivating vectors (ARV) have several advantages compared to other vector platforms, including a more random genomic integration pattern and reduced likelihood for inducing aberrant splicing of integrated proviruses. We developed an ARV platform for the transduction of primary human T lymphocytes. We demonstrated functional transgene transfer using the clinically relevant herpes-simplex-virus thymidine kinase variant TK.007. Proof-of-concept of alpharetroviral-mediated T-lymphocyte engineering was shown in vitro and in a humanized transplantation model in vivo. Furthermore, we established a stable, human alpharetroviral packaging cell line in which we deleted the entry receptor (SLC1A5) for RD114/TR-pseudotyped ARVs to prevent superinfection and enhance genomic integrity of the packaging cell line and viral particles. We showed that superinfection can be entirely prevented, while maintaining high recombinant virus titers. Taken together, this resulted in an improved production platform representing an economic strategy for translating the promising features of ARVs for therapeutic T-lymphocyte engineering.

  • 5.
    Novikov, Lev N
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Novikova, Liudmila N
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Mosahebi, Afshin
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Terenghi, Giorgio
    Kellerth, Jan-Olof
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    A novel biodegradable implant for neuronal rescue and regeneration after spinal cord injury.2002In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 23, no 16, p. 3369-76Article in journal (Refereed)
    Abstract [en]

    After spinal cord injury, the severed neuronal pathways fail to regenerate spontaneously. This study describes a biodegradable implant using poly-beta-hydroxybutyrate (PHB) fibers as carrier scaffold for matrix components and cell lines supporting neuronal survival and regeneration after spinal cord injury. After cervical spinal cord injury in adult rats, a graft consisting of PHB fibers coated with alginate hydrogel + fibronectin was implanted in the lesion cavity. In control groups, PHB was omitted and only alginate hydrogel or fibronectin, or their combination, were used for grafting. In addition, comparisons were made with animals treated intrathecally after spinal cord injury with the neurotrophic factors BDNF or NT-3. The neurons of the rubrospinal tract served as experimental model. In untreated animals, 45% of the injured rubrospinal neurons were lost at 8 weeks postoperatively. Implantation of the PHB graft reduced this cell loss by 50%, a rescuing effect similar to that obtained after treatment with BDNF or NT-3. In the absence of PHB support, implants of only alginate hydrogel or fibronectin, or their combination, had no effect on neuronal survival. After addition of neonatal Schwann cells to the PHB graft, regenerating axons were seen to enter the graft from both ends and to extend along its entire length. These results show that implants using PHB as carrier scaffold and containing alginate hydrogel, fibronectin and Schwann cells can support neuronal survival and regeneration after spinal cord injury

  • 6.
    Novikova, Liudmila N
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Pettersson, Jonas
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Brohlin, Maria
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Novikov, Lev N
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Biodegradable poly-beta-hydroxybutyrate scaffold seeded with Schwann cells to promote spinal cord repair2008In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 29, no 9, p. 1198-1206Article in journal (Refereed)
    Abstract [en]

    Cavity formation is an important obstacle impeding regeneration after spinal cord injury and bridging strategies are essential to provide physical substrate allowing axons to grow across the lesion site. In this study we evaluated effects of biodegradable tubular conduit made from poly-beta-hydroxybutyrate (PHB) scaffold with predominantly unidirectional fiber orientation and supplemented with cultured adult Schwann cells on axonal regeneration after cervical spinal cord injury in adult rats. After transplantation into the injured spinal cord, plain PHB conduit was well-integrated into posttraumatic cavity and induced modest astroglial reaction. Regenerating axons were found mainly outside the PHB with only single fibers crossing the host-graft interface. No host Schwann cells migrated into the graft. In contrast, when suspension of adult Schwann cells was added to the PHB during transplantation, neurofilament-positive axons filled the conduit and became associated with the implanted cells. Although rubrospinal fibers did not enter the PHB, numerous raphaespinal and CGRP-positive axons were found within the conduit. Modification of PHB surface with fibronectin, laminin or collagen significantly increased Schwann cell attachment and proliferation in vitro. However, transplantation of PHB conduit pre-coated with fibronectin and seeded with Schwann cells did not alter axonal growth response. The results demonstrate that a PHB scaffold promotes attachment, proliferation and survival of adult Schwann cells and supports marked axonal regeneration within the graft.

  • 7.
    Ouasti, Sihem
    et al.
    University of Manchester.
    Kingham, Paul J
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. University of Manchester.
    Terenghi, Giorgio
    University of Manchester.
    Tirelli, Nicola
    University of Manchester.
    The CD44/integrins interplay and the significance of receptor binding and re-presentation in the uptake of RGD-functionalized hyaluronic acid2012In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 33, no 4, p. 1120-1134Article in journal (Refereed)
    Abstract [en]

    We have studied the interplay between two endocytic receptors for a carrier structure bearing two complementary ligands. Hyaluronic acid (HA; three different molecular weights) was functionalized with an RGD-containing peptide; this ancillary ligand allows the macromolecule to bind to alpha(v) integrins in addition to the classical HA internalization receptor (CD44). The uptake of HA-RGD and of native HA was assessed in a phagocytic cell model (J774.2 murine macrophages), studying the kinetics of internalization and its mechanistic details. Indications of a synergic binding to integrins and CD44 emerged for HA-RGD; possibly, a first binding to integrins allows for a pre-concentration of the macromolecule on the cell surface, which is then followed by its binding to CD44. The endocytic mechanism and kinetics appeared then dominated by CD44, which has a much slower turnover than integrins. In this study we have demonstrated that the knowledge of the rate-determining steps of the internalization of a carrier is necessary for assessing its performance. In this case, the presence of multiple ligands on a carrier was beneficial in some respect (e.g. in improved binding/targeting), but may not be sufficient to overcome penetration barriers that arise from slow receptor re-presentation. (C) 2011 Elsevier Ltd. All rights reserved.

  • 8.
    Persson-Sjögren, Solveig
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Sjögren, Göran
    Umeå University, Faculty of Medicine, Department of Odontology, Dental Materials Science.
    Effects of glass ionomers and dental resin composites on viability of beta-cells and insulin release in isolated islets of Langerhans.2003In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 24, no 21, p. 3741-3746Article in journal (Refereed)
    Abstract [en]

    Information on the biocompatibility of glass ionomers and resin composites is sparse. To extend the scale of biological testing we evaluated the influence of those materials on insulin secretion at whole organ level in vitro. The effects on insulin secretion of three glass ionomers and two resin composites, aged for 1 week, were studied in isolated mouse islets of Langerhans at basal (5.5mM) and at stimulatory (11.1mM) D-glucose concentrations. In addition, viability of single mouse beta-cells was evaluated. The effect of glass ionomer specimens aged for 1 and 4 months on insulin secretion at 11.1mM D-glucose was also studied. None of the materials affected the viability of the beta-cells. At 5.5mM D-glucose none of the materials affected the insulin secretion. At 11.1mM D-glucose, the glass ionomers only decreased the secretion and glass ionomers aged for 1 month still decreased insulin release whereas after 4 months ageing only one of the glass ionomers affected the release. The result shows a dynamic effect on insulin release of the elements and/or compounds released from the specimens.

  • 9. Raina, Deepak Bushan
    et al.
    Qayoom, Irfan
    Larsson, David
    Umeå University, Faculty of Medicine. Lund University, Faculty of Medicine, Department of Clinical Sciences Lund, Orthopedics, Lund 22185, Sweden.
    Zheng, Ming Hao
    Kumar, Ashok
    Isaksson, Hanna
    Lidgren, Lars
    Tagil, Magnus
    Guided tissue engineering for healing of cancellous and cortical bone using a combination of biomaterial based scaffolding and local bone active molecule delivery2019In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 188, p. 38-49Article in journal (Refereed)
    Abstract [en]

    A metaphyseal bone defect due to infection, tumor or fracture leads to loss of cancellous and cortical bone. An animal model separating the cancellous and cortical healing was used with a combination of a macroporous gelatin-calcium sulphate-hydroxyapatite (Gel-CaS-HA) biomaterial as a cancellous defect filler, and a thin collagen membrane (CM) guiding cortical bone regeneration. The membrane was immobilized with bone morphogenic protein-2 (rhBMP-2) to enhance the osteoinductive properties. The Gel-CaS-HA cancellous defect filler contained both rhBMP-2 and a bisphosphonate, (zoledronate = ZA) to prevent premature callus resorption induced by the pro-osteoclast effect of rhBMP-2 alone. In the first part of the study, the CM delivering both rhBMP-2 and ZA was tested in a muscle pouch model in rats and the co-delivery of rhBMP-2 and ZA via the CM resulted in higher amounts of bone compared to rhBMP-2 alone. Secondly, an established tibia defect model in rats was used to study cortical and cancellous bone regeneration. The defect was left empty, filled with Gel-CaS-HA alone, Gel-CaS-HA immobilized with ZA or Gel-CaS-HA immobilized with rhBMP-2+ ZA. Functionalization of the Gel-CaS-HA scaffold with bioactive molecules produced significantly more bone in the cancellous defect and its surroundings but cortical defect healing was delayed likely due to the protrusion of the Gel-CaS-HA into the cortical bone. To guide cortical regeneration, the cortical defect was sealed endosteally by a CM with or without rhBMP-2. Subsequently, the cancellous defect was filled with Gel-CaS-HA containing ZA and rhBMP2 + ZA. In the groups where the CM was doped with rhBMP-2, significantly higher number of cortices bridged. The approach to guide cancellous as well as cortical bone regeneration separately in a metaphyseal defect using two bioactive molecule immobilized biomaterials is promising and could improve the clinical care of patients with metaphyseal defects.

  • 10. Wang, Xuefeng
    et al.
    Ohlin, Christian A.
    Lu, Qinghua
    Hu, Jun
    Cell directional migration and oriented division on three-dimensional laser-induced periodic surface structures on polystyrene2008In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 29, no 13, p. 2049-2059Article in journal (Refereed)
    Abstract [en]

    The extracellular matrix in animal tissues usually provides a three-dimensional structural support to cells in addition to performing various other important functions. In the present study, wavy submicrometer laser-irradiated periodic surface structures (LIPSS) were produced on a smooth polystyrene film by polarized laser irradiation with a wavelength of 266 nm. Rat C6 glioma cells exhibited directional migration and oriented division on laser-irradiated polystyrene, which was parallel to the direction of LIPSS. However, rat C6 glioma cells on smooth polystyrene moved in a three-step invasion cycle, with faster migation speed than that on laser-irradiated polystyrene. In addition, focal adhesions examined by immunostaining focal adhesion kinase in human epithelial carcinoma HeLa cells were punctuated on smooth polystyrene, whereas dash-like on laser-irradiated polystyrene. We hypothesized that LIPSS on laser-irradiated polystyrene acted as an anisotropic and persistent mechanical stimulus to guide cell anisotropic spreading, migration and division through focal adhesions.

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