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  • 1.
    Alarcon, E I
    et al.
    Bio-nanomaterials Chemistry and Engineering Laboratory, Division of Cardiac Surgery, University of Ottawa Heart Institute, 40 Ruskin Street, Rm H5229, Ottawa, Canada.
    Vulesevic, B
    Bio-nanomaterials Chemistry and Engineering Laboratory, Division of Cardiac Surgery, University of Ottawa Heart Institute, 40 Ruskin Street, Rm H5229, Ottawa, Canada.
    Argawal, A
    Bio-nanomaterials Chemistry and Engineering Laboratory, Division of Cardiac Surgery, University of Ottawa Heart Institute, 40 Ruskin Street, Rm H5229, Ottawa, Canada.
    Ross, A
    Bio-nanomaterials Chemistry and Engineering Laboratory, Division of Cardiac Surgery, University of Ottawa Heart Institute, 40 Ruskin Street, Rm H5229, Ottawa, Canada.
    Bejjani, P
    Bio-nanomaterials Chemistry and Engineering Laboratory, Division of Cardiac Surgery, University of Ottawa Heart Institute, 40 Ruskin Street, Rm H5229, Ottawa, Canada.
    Podrebarac, J
    Bio-nanomaterials Chemistry and Engineering Laboratory, Division of Cardiac Surgery, University of Ottawa Heart Institute, 40 Ruskin Street, Rm H5229, Ottawa, Canada.
    Ravichandran, Ranjithkumar
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
    Phopase, Jaywant
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
    Suuronen, E J
    Bio-nanomaterials Chemistry and Engineering Laboratory, Division of Cardiac Surgery, University of Ottawa Heart Institute, 40 Ruskin Street, Rm H5229, Ottawa, Canada.
    Griffith, May
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Coloured cornea replacements with anti-infective properties: expanding the safe use of silver nanoparticles in regenerative medicine.2016In: Nanoscale, ISSN 2040-3364, E-ISSN 2040-3372, Vol. 8, no 12, p. 6484-6489Article in journal (Refereed)
    Abstract [en]

    Despite the broad anti-microbial and anti-inflammatory properties of silver nanoparticles (AgNPs), their use in bioengineered corneal replacements or bandage contact lenses has been hindered due to their intense yellow coloration. In this communication, we report the development of a new strategy to pre-stabilize and incorporate AgNPs with different colours into collagen matrices for fabrication of corneal implants and lenses, and assessed their in vitro and in vivo activity.

  • 2. Order onlineBuy this publication >>
    Aronsson, Christopher
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
    Tunable and modular assembly of polypeptides and polypeptide-hybrid biomaterials2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Biomaterials are materials that are specifically designed to be in contact with biological systems and have for a long time been used in medicine. Examples of biomaterials range from sophisticated prostheses used for replacing outworn body parts to ordinary contact lenses. Currently it is possible to create biomaterials that can e.g. specifically interact with cells or respond to certain stimuli. Peptides, the shorter version of proteins, are excellent molecules for fabrication of such biomaterials. By following and developing design rules it is possible to obtain peptides that can self-assemble into well-defined nanostructures and biomaterials.

    The aim of this thesis is to create ”smart” and tunable biomaterials by molecular self-assembly using dimerizing –helical polypeptides. Two different, but structurally related, polypeptide-systems have been used in this thesis. The EKIV-polypeptide system was developed in this thesis and consists of four 28-residue polypeptides that can be mixed-and-matched to self-assemble into four different coiled coil heterodimers. The dissociation constant of the different heterodimers range from μM to < nM. Due to the large difference in affinities, the polypeptides are prone to thermodynamic social self-sorting. The JR-polypeptide system, on the other hand, consists of several 42-residue de novo designed helix-loop-helix polypeptides that can dimerize into four-helix bundles. In this work, primarily the glutamic acid-rich polypeptide JR2E has been explored as a component in supramolecular materials. Dimerization was induced by exposing the polypeptide to either Zn2+, acidic conditions or the complementary polypeptide JR2K.

    By conjugating JR2E to hyaluronic acid and the EKIV-polypeptides to star-shaped poly(ethylene glycol), respectively, highly tunable hydrogels that can be self-assembled in a modular fashion have been created. In addition, self-assembly of spherical superstructures has been investigated and were obtained by linking two thiol-modified JR2E polypeptides via a disulfide bridge in the loop region. ŒThe thesis also demonstrates that the polypeptides and the polypeptide-hybrids can be used for encapsulation and release of molecules and nanoparticles. In addition, some of the hydrogels have been explored for 3D cell culture. By using supramolecular interactions combined with bio-orthogonal covalent crosslinking reactions, hydrogels were obtained that enabled facile encapsulation of cells that retained high viability.

    The results of the work presented in this thesis show that dimerizing α–helical polypeptides can be used to create modular biomaterials with properties that can be tuned by specific molecular interactions. The modularity and the tunable properties of these smart biomaterials are conceptually very interesting andmake them useful in many emerging biomedical applications, such as 3D cell culture, cell therapy, and drug delivery

    .

    List of papers
    1. Self-sorting heterodimeric coiled coil peptides with defined and tuneable self-assembly properties
    Open this publication in new window or tab >>Self-sorting heterodimeric coiled coil peptides with defined and tuneable self-assembly properties
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    2015 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 5, no 14063Article in journal (Refereed) Published
    Abstract [en]

    Coiled coils with defined assembly properties and dissociation constants are highly attractive components in synthetic biology and for fabrication of peptide-based hybrid nanomaterials and nanostructures. Complex assemblies based on multiple different peptides typically require orthogonal peptides obtained by negative design. Negative design does not necessarily exclude formation of undesired species and may eventually compromise the stability of the desired coiled coils. This work describe a set of four promiscuous 28-residue de novo designed peptides that heterodimerize and fold into parallel coiled coils. The peptides are non-orthogonal and can form four different heterodimers albeit with large differences in affinities. The peptides display dissociation constants for dimerization spanning from the micromolar to the picomolar range. The significant differences in affinities for dimerization make the peptides prone to thermodynamic social self-sorting as shown by thermal unfolding and fluorescence experiments, and confirmed by simulations. The peptides self-sort with high fidelity to form the two coiled coils with the highest and lowest affinities for heterodimerization. The possibility to exploit self-sorting of mutually complementary peptides could hence be a viable approach to guide the assembly of higher order architectures and a powerful strategy for fabrication of dynamic and tuneable nanostructured materials.

    Place, publisher, year, edition, pages
    NATURE PUBLISHING GROUP, 2015
    National Category
    Physical Sciences Electrical Engineering, Electronic Engineering, Information Engineering
    Identifiers
    urn:nbn:se:liu:diva-121739 (URN)10.1038/srep14063 (DOI)000361177400001 ()26370878 (PubMedID)
    Note

    Funding Agencies|Swedish Research Council (VR); Swedish Foundation for Strategic Research (SSF)

    Available from: 2015-10-06 Created: 2015-10-05 Last updated: 2022-09-15
    2. Tailoring Supramolecular Peptide-Poly(ethylene glycol) Hydrogels by Coiled Coil Self-Assembly and Self-Sorting
    Open this publication in new window or tab >>Tailoring Supramolecular Peptide-Poly(ethylene glycol) Hydrogels by Coiled Coil Self-Assembly and Self-Sorting
    2016 (English)In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 17, no 6, p. 2260-2267Article in journal (Refereed) Published
    Abstract [en]

    Physical hydrogels are extensively used in a wide range of biomedical applications. However, different applications require hydrogels with different mechanical and structural properties. Tailoring these properties demands exquisite control over the supramolecular peptides with different affinities for dimerization. Four different mechanical properties of hydrogels using de novo designed coiled coil interactions involved. Here we show that it is possible to control the nonorthogonal peptides, designed to fold into four different coiled coil heterodimers with dissociation constants spanning from mu M to pM, were conjugated to star-shaped 4-arm poly(ethylene glycol) (PEG). The different PEG-coiled coil conjugates self-assemble as a result of peptide heterodimerization. Different combinations of PEG peptide conjugates assemble into PEG peptide networks and hydrogels with distinctly different thermal stabilities, supramolecular, and rheological properties, reflecting the peptide dimer affinities. We also demonstrate that it is possible to rationally modulate the self-assembly process by means of thermodynamic self-sorting by sequential additions of nonpegylated peptides. The specific interactions involved in peptide dimerization thus provides means for programmable and reversible self-assembly of hydrogels with precise control over rheological properties, which can significantly facilitate optimization of their overall performance and adaption to different processing requirements and applications.

    Place, publisher, year, edition, pages
    AMER CHEMICAL SOC, 2016
    National Category
    Polymer Chemistry
    Identifiers
    urn:nbn:se:liu:diva-130135 (URN)10.1021/acs.biomac.6b00528 (DOI)000377924800038 ()27219681 (PubMedID)
    Note

    Funding Agencies|Swedish Research Council [621-2011-4319]; Swedish Foundation for Strategic Research [ICA10-0002]; Linkoping University; Swedish Government Strategic Research Area in Materials Science on Functional Materials at Linkoping University (Faculty Grant SFO-Mat-LiU) [2009 00971]

    Available from: 2016-07-12 Created: 2016-07-11 Last updated: 2019-01-22
    3. Zinc-Triggered Hierarchical Self-Assembly of Fibrous Helix-Loop-Helix Peptide Superstructures for Controlled Encapsulation and Release
    Open this publication in new window or tab >>Zinc-Triggered Hierarchical Self-Assembly of Fibrous Helix-Loop-Helix Peptide Superstructures for Controlled Encapsulation and Release
    2016 (English)In: Macromolecules, ISSN 0024-9297, E-ISSN 1520-5835, Vol. 49, no 18, p. 6997-7003Article in journal (Refereed) Published
    Abstract [en]

    We demonstrate a novel route for hierarchical self-assembly of sub-micrometer-sized peptide superstructures that respond to subtle changes in Zn2+ concentration. The self-assembly process is triggered by a specific folding-dependent coordination of Zn2+ by a de novo designed nonlinear helix-loop-helix peptide, resulting in a propagating fiber formation and formation of spherical superstructures. The superstructures further form larger assemblies that can be completely disassembled upon removal of Zn2+ or degradation of the nonlinear peptide. This flexible and reversible assembly strategy of the superstructures enables facile encapsulation of nanoparticles and drugs that can be released by means of different stimuli.

    Place, publisher, year, edition, pages
    AMER CHEMICAL SOC, 2016
    National Category
    Polymer Chemistry
    Identifiers
    urn:nbn:se:liu:diva-132215 (URN)10.1021/acs.macromol.6b01724 (DOI)000384399100030 ()
    Note

    Funding Agencies|Swedish Research Council [621-2011-4319]; Swedish Foundation for Strategic Research [ICA10-0002]; Linkoping University; Swedish Government Strategic Research Area in Materials Science on Functional Materials at Linkoping University [2009 00971]

    Available from: 2016-10-26 Created: 2016-10-21 Last updated: 2019-01-22
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  • 3.
    Aronsson, Henrik
    Linköping University, The Department of Physics, Chemistry and Biology.
    Local Delivery of Bisphosphonates from FibMat Matrix2008Independent thesis Basic level (professional degree), 20 points / 30 hpStudent thesis
    Abstract [en]

    Improving the functionality and reducing revision rates are important driving forces in the development of orthopaedic implants. FibMat is a fibrinogen based matrix developed towards commercialisation by the company Optovent AB. This matrix can be coated on implants and act as a local drug delivery system for bisphosphonates (BPs). BPs are drugs inhibiting bone resorption, and applied with FibMat to improve stability of implants in bone, e.g. when fixing bone fractures. In this thesis, FibMat loaded with BP (FibMat/BP) was coated on stainless-steel screws and titanium screws in order to investigate some technology properties relevant to its clinical applicability. Bone-mimicking materials were used to study scrape-off effect upon insertion. The coagulation properties of fibrinogen as well as the structural properties of BPs were studied after exposure to gamma radiation.

    The screws were coated with FibMat and BP (alendronate and 14C-alendronate) using standard coupling techniques. The total amount and distribution of BP after insertion was measured by liquid scintillation and autoradiography. Coagulation assays were performed in order to determine the coagulation properties of fibrinogen, exposed to doses up to 35 kGy, mixed with thrombin. The structural properties of four different BPs (alendronate, pamidronate, zoledronate and ibandronate), exposed to doses up to 35 kGy were analysed by transmission infrared spectroscopy.

    The results show that FibMat/BP coating on porous stainless-steel screws is virtually unaffected by insertion into bone materials. The anodised, planar titanium screws are more affected by the insertion process, but an even BP distribution in the cancellous material is indicated. The coagulation assays show that gamma-irradiated fibrinogen has a slower coagulation process compared to non-irradiated fibrinogen and form interrupted network unable to clot. The chemical structures of the BPs seem unaffected by exposure to gamma irradiation. In conclusion, the FibMat/BP is a promising technology for local distribution of BP in conjunction with bone implants.

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  • 4.
    Blomgran, Parmis
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Hammerman, Malin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Aspenberg, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Orthopaedics in Linköping.
    Systemic corticosteroids improve tendon healing when given after the early inflammatory phase2017In: Scientific Reports, E-ISSN 2045-2322, Vol. 7, article id 12468Article in journal (Refereed)
    Abstract [en]

    Inflammation initiates tendon healing and then normally resolves more or less completely. Unresolved inflammation might disturb the remodeling process. We hypothesized that suppression of inflammation during the early remodeling phase by systemic dexamethasone treatment can improve healing. 36 rats underwent Achilles tendon transection and were randomized to dexamethasone or saline on days 0-4 after surgery (early inflammatory phase), and euthanasia day 7. Another 54 rats received injections days 5-9 (early remodeling phase) and were euthanized day 12 for mechanical, histological and flow cytometric evaluation. Dexamethasone treatment days 0-4 reduced the cross-sectional area, peak force and stiffness by day 7 to less than half (p amp;lt; 0.001 for all), while material properties (peak stress and elastic modulus) were not significantly affected. In contrast, dexamethasone treatment days 5-9 increased peak force by 39% (p = 0.002) and stiffness by 58% (p amp;lt; 0.001). The cross-sectional area was reduced by 42% (p amp;lt; 0.001). Peak stress and elastic modulus were more than doubled (p amp;lt; 0.001 for both). Semi-quantitative histology at day 12 showed that late dexamethasone treatment improved collagen alignment, and flow cytometry revealed reduced numbers of CD8a(+) cytotoxic T cells in the tendon callus. These results suggest that downregulation of lingering inflammation during the early remodeling phase can improve healing.

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  • 5.
    Broitman, Esteban
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Thin Film Physics. Linköping University, The Institute of Technology.
    Bojorge, C
    CINSO, Argentina.
    Elhordoy, F
    Instituto de Física & CINQUIFIMA, Uruguay.
    Kent, V.
    Instituto de Física & CINQUIFIMA, Uruguay.
    Zanini Gadioli, G
    Instituto de Física Gleb Wataghin, Brazil.
    Marotti, R.
    Instituto de Física & CINQUIFIMA, Uruguay.
    Canepa, H
    CINSO, Argentina.
    Dalchiele, E. A.
    Instituto de Física & CINQUIFIMA, Uruguay.
    Comparative study on the properties of ZnO nanowires and nanocrystalline thin films2012In: Surface & Coatings Technology, ISSN 0257-8972, E-ISSN 1879-3347, Vol. 213, p. 59-64Article in journal (Refereed)
    Abstract [en]

    The microstructural, morphological, optical and water-adsorption properties of nanocrystalline ZnO thin films and ZnO nanowires were studied and compared. The ZnO thin films were obtained by a sol–gel process, while the ZnO nanowires were electrochemically grown onto a ZnO sol–gel spin-coated seed layer. Thin films and nanowire samples were deposited onto crystalline quartz substrates covered by an Au electrode, able to be used in a quartz crystal microbalance. X-ray diffraction measurements reveal in both cases a typical diffraction pattern of ZnO wurtzite structure. Scanning electron microscopic images of nanowire samples show the presence of nanowires with hexagonal sections, with diameters ranging from 30 to 90 nm. Optical characterization reveals a bandgap energy of 3.29 eV for the nanowires and 3.35 eV for the thin films. A quartz crystal microbalance placed in a vacuum chamber was used to quantify the amount and kinetics of water adsorption onto the samples. Nanowire samples, which have higher surface areas than the thin films, adsorb significantly more water.

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  • 6.
    Broitman, Esteban
    et al.
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, Faculty of Science & Engineering.
    Nedelcu, Dumitru
    Gheorghe Asachi Tech Univ Iasi, Romania.
    Special Issue on: Modern Technologies as Future Solutions for Performance Products Introduction2018In: International journal of materials & product technology, ISSN 0268-1900, E-ISSN 1741-5209, Vol. 56, no 1-2Article in journal (Other academic)
    Abstract [en]

    n/a

  • 7.
    Brunette, Isabelle
    et al.
    University of Montreal, Canada.
    Alarcon, Emilio
    University of Ottawa Heart Institute, Canada.
    Griffith, May
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Cornea Regeneration as an Alternative to Human Donor Transplantation2015In: European Ophthalmic Review, ISSN 1756-1795, Vol. 9, no 2, p. 111-114Article in journal (Refereed)
    Abstract [en]

    There is a need for an alternative to human donor corneas as the availability of good-quality tissues remains limited, with this situation potentially worsening as the population in many countries is progressively ageing. There have been numerous attempts to develop corneal equivalent as alternatives to donated human corneas as well as prostheses. In this short review, we focus on the efforts in bioengineering implants that promote regeneration by Canadian researchers, including our current team of authors. The examples of technologies developed that we describe include biomaterials that allow for partial regeneration of corneal tissue, self-assembled cornea constructs and cell-free corneal implants that promoted regeneration when evaluated in clinical trials in Europe.

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    fulltext
  • 8.
    Buznyk, Oleksiy
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Sensory Organs and Communication. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping. NAMS Ukraine, Ukraine.
    Azharuddin, Mohammad
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Islam, Mohammad Mirazul
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Harvard Univ, MA 02114 USA.
    Fagerholm, Per
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Sensory Organs and Communication. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Pasyechnikova, Nataliya
    NAMS Ukraine, Ukraine.
    Patra, Hirak K.
    Univ Cambridge, England; Univ Cambridge, England.
    Collagen-based scaffolds with infused anti-VEGF release system as potential cornea substitute for high-risk keratoplasty: A preliminary in vitro evaluation2020In: Heliyon, E-ISSN 2405-8440, Vol. 6, no 10, article id e05105Article in journal (Refereed)
    Abstract [en]

    Currently the only widely accepted corneal blindness treatment is human donor cornea transplantation. However, increasing shortage of donor corneas as well as high risk of rejection in some corneal diseases remain two major problems, which limit the success of corneal transplantation. Corneal neovascularization is considered as one of the main risk factors of graft failure. Different cell-free biosynthetic scaffolds fabricated from collagens or collagen-like peptides are being tested as donor cornea substitutes (DCS). Here, we report for the first-time composite biosynthetic DCS with integrated sustained release system of anti-VEGF drug, bevacizumab and their preliminary in vitro validation. We have tethered gold nanoparticles with bevacizumab and integrated into a collagen-based cell-free hydrogel scaffold. Developed grafts preserved good optical properties and were confirmed not toxic to human corneal epithelial cells. Bevacizumab has been shown to constantly releasing from the DCS up to 3 weeks and preserved its anti-angiogenic properties. These results provide background for further use of infused composite biosynthetic DCS with integrated nanosystem of bevacizumab sustained release in corneal disease accompanied by neovascularisation where conventional corneal transplantation might fail.

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    fulltext
  • 9.
    Bäcklund, Fredrik G.
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics. Linköping University, Faculty of Science & Engineering.
    Pallbo, Jon
    Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics. Linköping University, Faculty of Science & Engineering.
    Solin, Niclas
    Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics. Linköping University, Faculty of Science & Engineering.
    Controlling Amyloid Fibril Formation by Partial Stirring2016In: Biopolymers, ISSN 0006-3525, E-ISSN 1097-0282, Vol. 105, no 5, p. 249-259Article in journal (Refereed)
    Abstract [en]

    Many proteins undergoes self-assembly into fibrillar structures known as amyloid fibrils. During the self-assembly process related structures, known as spherulites, can be formed. Herein we report a facile method where the balance between amyloid fibrils and spherulites can be controlled by stirring of the reaction mixture during the initial stages of the self-assembly process. Moreover, we report how this methodology can be used to prepare non-covalently functionalized amyloid fibrils. By stirring the reaction mixture continuously or for a limited time during the lag phase the fibril length, and hence the propensity to form liquid crystalline phases, can be influenced. This phenomena is utilized by preparing films consisting of aligned protein fibrils incorporating the laser dye Nile red. The resulting films display polarized Nile red fluorescence.

  • 10.
    Bäcklund, Fredrik G.
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics. Linköping University, Faculty of Science & Engineering.
    Solin, Niclas
    Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics. Linköping University, Faculty of Science & Engineering.
    Tuning the aqueous self-assembly process of insulin by a hydrophobic additive2015In: RSC ADVANCES, ISSN 2046-2069, Vol. 5, no 112, p. 92254-92262Article in journal (Refereed)
    Abstract [en]

    Biomolecular self-assembly is an efficient way of preparing soft-matter based materials. Herein we report a novel method, based on the use of insoluble additives in aqueous media, for influencing the self-assembly process. Due to their low solubility, the use of hydrophobic additives in aqueous media is problematic; however, by mixing the additive with the biomolecule in the solid state, prior to solvation, this problem can be circumvented. In the investigated self-assembly system, where bovine insulin self-assembles into spherical structures, the inclusion of the hydrophobic material α-sexithiophene (6T) results in significant changes in the self-assembly process. Under our reaction conditions, in the case of materials prepared from insulin-only the growth of spherulites typically stops at a diameter of 150μm. However, by adding 2 weight % of hydrophobic material, spherulite growth continues up to diameters in the mm-range. The spherulites incorporate 6T and are thus fluorescent. The method reported herein should be of interest to all scientists working in the field of self-assembly as the flexible materials preparation, based simply on co-grinding of commercially available materials, adds another option to influence the structure and properties of products formed by  self-assembly reactions.

  • 11.
    Bäcklund, Fredrik Gustaf
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics. Linköping University, Faculty of Science & Engineering.
    Ajjan, Fátima Nadia
    Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics. Linköping University, Faculty of Science & Engineering.
    Solin, Niclas
    Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics. Linköping University, Faculty of Science & Engineering.
    Convection Induced Air-Water Interface Assembly of Amyloid FibrilsManuscript (preprint) (Other academic)
    Abstract [en]

    We report that hydrophobically modified amyloid fibrils form macroscopic films at the air-water interface. The hydrophobically modified fibrils are prepared in a two step process. First bovine insulin is ground with a hydrophobic compound. The resulting material is dissolved in acidic water and heated to induce assembly into fibrils incorporating the hydrophobic compounds. Upon dilution followed by asymmetric heating, resulting in convection flow, the fibrills form highly ordered films with thicknesses from 80 nm and up. The thickness of the film can be controlled by the fibril concentration and/or reaction time. The films contain anisotropic domains spanning several square centimeters. In addition, the films contains ordered assemblies of dyes that display emission of polarized light.

  • 12.
    Cardemil, Carina
    Department of Biomaterials, Institute of Clinical Sciences, The Sahlgrenska Academy at the University of Gothenburg, Göteborg, Sweden.
    Effects of antiresorptive agents on inflammation and bone regeneration in different osseous sites - experimental and clinical studies2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The biological mechanisms involved in bone regeneration in osteoporotic bone and the effect of antiresorptive drugs in relation to surgically inserted biomaterials are not fully understood. Improved osseointegration of titanium implants but also adverse effects of antiresorptive therapies, such as osteonecrotic jaw have been described in the literature. The aims of this research project were, firstly, to investigate and to understand the biological events determining bone regeneration and implant integration, after administration of antiresorptive agents; secondly, to determine the cellular and molecular patterns of bone regeneration at implants and synthetic bone substitutes under osteoporotic conditions and, thirdly, to determine how different skeletal sites are affected. The present research included a study of jawbone morphology and gene expression in patients treated with systemic bisphosphonates. When compared to controls, higher gene expression levels of IL-1β was observed in bisphosphonate treated patients with osteonecrosis while bisphosphonate treated patients without necrosis showed lower expression levels of caspase 8, an apoptosis marker involved in the immune response. In ovariectomised rats, zoledronic acid resulted in site-specific differences in the rate of osseointegration and also of gene expression involved in bone healing and regeneration. Strontium-doped calcium phosphate inserted in the rat femur induced lower expression of osteoclastic markers compared to hydroxyapatite and higher bone formation in the periphery of the defects. Whereas major structural changes were demonstrated in the long bones of the ovariectomised rat, less structural alterations were shown in the mandible. However, ovariectomy resulted in lower expression of genes coding for bone formation and angiogenesis in the mandible. In conclusion, the present study shows that the mandible is differently affected by experimentally induced estrogen deficiency than the long bones. Bisphosphonates, administered systemically to estrogen deficient animals, impair osseointegration in the mandible, at least partly related to a downregulation of genes important for the osteogenic process. These observations may have implications for understanding the mechanisms involved in the deranged bone healing observed in the jawbone of bisphosphonate treated patients.

    List of papers
    1. The effects of a systemic single dose of zoledronic acid on post-implantation bone remodelling and inflammation in an ovariectomised rat model.
    Open this publication in new window or tab >>The effects of a systemic single dose of zoledronic acid on post-implantation bone remodelling and inflammation in an ovariectomised rat model.
    Show others...
    2013 (English)In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 34, no 5, p. 1546-1561Article in journal (Refereed) Published
    Abstract [en]

    Bisphosphonates reverse the negative effects of ovariectomy on bone, but they have also been associated with adverse processes in human jawbone. The molecular events determining bone regeneration and implant integration in osteoporotic conditions, with and without bisphosphonate treatment, are unclear. In this study, ovariectomised rats, to which a single dose of saline (NaCl) or zoledronic acid (Zol) was administered, received titanium alloy implants in their tibiae and mandibles. An enzyme-linked immunosorbent assay, gene expression analysis and histomorphometry were performed. The results show that ovariectomy, per se, upregulated the expression of genes denoting bone formation in the tibia, bone remodelling in the mandible and apoptosis in the tibia and mandible. Zoledronic acid administration resulted in lower levels of a remodelling marker in serum and downregulated gene expression for inflammation, bone formation, angiogenesis and apoptosis, mainly in the mandible, after 28 d of healing. Histomorphometry revealed improved bone-to-implant contact in the tibia, while the opposite was observed in the mandible. The present data show that a systemic single dose of zoledronic acid, in ovariectomised animals, results in site-specific differences in the regulation of genes involved in bone healing and regeneration in association with implant installation. These events occur in parallel with site-specific differences in the rate of osseointegration, indicating diverse tissue responses in the tibia and mandible after zoledronic acid treatment. The zoledronic acid effect on gene expression, during the late phase of healing in the mandible, suggests negative effects by the anti-resorptive agent on osseointegration at that particular site.

    National Category
    Basic Medicine
    Identifiers
    urn:nbn:se:liu:diva-135755 (URN)10.1016/j.biomaterials.2012.11.003 (DOI)23182921 (PubMedID)
    Available from: 2017-03-21 Created: 2017-03-21 Last updated: 2018-01-13
    2. Strontium-doped calcium phosphate and hydroxyapatite granules promote different inflammatory and bone remodelling responses in normal and ovariectomised rats
    Open this publication in new window or tab >>Strontium-doped calcium phosphate and hydroxyapatite granules promote different inflammatory and bone remodelling responses in normal and ovariectomised rats
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    2013 (English)In: PLOS ONE, E-ISSN 1932-6203, Vol. 8, no 12, article id e84932Article in journal (Refereed) Published
    Abstract [en]

    The healing of bone defects may be hindered by systemic conditions such as osteoporosis. Calcium phosphates, with or without ion substitutions, may provide advantages for bone augmentation. However, the mechanism of bone formation with these materials is unclear. The aim of this study was to evaluate the healing process in bone defects implanted with hydroxyapatite (HA) or strontium-doped calcium phosphate (SCP) granules, in non-ovariectomised (non-OVX) and ovariectomised (OVX) rats. After 0 (baseline), six and 28d, bone samples were harvested for gene expression analysis, histology and histomorphometry. Tumour necrosis factor-α (TNF-α), at six days, was higher in the HA, in non-OVX and OVX, whereas interleukin-6 (IL-6), at six and 28d, was higher in SCP, but only in non-OVX. Both materials produced a similar expression of the receptor activator of nuclear factor kappa-B ligand (RANKL). Higher expression of osteoclastic markers, calcitonin receptor (CR) and cathepsin K (CatK), were detected in the HA group, irrespective of non-OVX or OVX. The overall bone formation was comparable between HA and SCP, but with topological differences. The bone area was higher in the defect centre of the HA group, mainly in the OVX, and in the defect periphery of the SCP group, in both non-OVX and OVX. It is concluded that HA and SCP granules result in comparable bone formation in trabecular bone defects. As judged by gene expression and histological analyses, the two materials induced different inflammatory and bone remodelling responses. The modulatory effects are associated with differences in the spatial distribution of the newly formed bone.

    National Category
    Biomaterials Science Medical Materials Medical Biotechnology Cell and Molecular Biology
    Identifiers
    urn:nbn:se:liu:diva-136113 (URN)10.1371/journal.pone.0084932 (DOI)24376855 (PubMedID)
    Available from: 2017-03-28 Created: 2017-03-28 Last updated: 2021-06-14Bibliographically approved
  • 13.
    Cardemil, Carina
    et al.
    Department of Biomaterials, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden, Department of Oral and Maxillofacial Surgery, Örebro University Hospital, Örebro, Sweden, BIOMATCELL VINN Excellence Center of Biomaterials and Cell Therapy, Gothenburg, Sweden .
    Elgali, Ibrahim
    Department of Biomaterials, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden, BIOMATCELL VINN Excellence Center of Biomaterials and Cell Therapy, Gothenburg, Sweden.
    Xia, Wei
    Applied Materials Science, Department of Engineering Sciences, Uppsala University, Uppsala, Sweden, BIOMATCELL VINN Excellence Center of Biomaterials and Cell Therapy, Gothenburg, Sweden.
    Emanuelsson, Lena
    Department of Biomaterials, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden, BIOMATCELL VINN Excellence Center of Biomaterials and Cell Therapy, Gothenburg, Sweden.
    Norlindh, Birgitta
    Department of Biomaterials, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden, BIOMATCELL VINN Excellence Center of Biomaterials and Cell Therapy, Gothenburg, Sweden.
    Omar, Omar
    Department of Biomaterials, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden, BIOMATCELL VINN Excellence Center of Biomaterials and Cell Therapy, Gothenburg, Sweden.
    Thomsen, Peter
    Department of Biomaterials, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden, BIOMATCELL VINN Excellence Center of Biomaterials and Cell Therapy, Gothenburg, Sweden .
    Strontium-doped calcium phosphate and hydroxyapatite granules promote different inflammatory and bone remodelling responses in normal and ovariectomised rats2013In: PLOS ONE, E-ISSN 1932-6203, Vol. 8, no 12, article id e84932Article in journal (Refereed)
    Abstract [en]

    The healing of bone defects may be hindered by systemic conditions such as osteoporosis. Calcium phosphates, with or without ion substitutions, may provide advantages for bone augmentation. However, the mechanism of bone formation with these materials is unclear. The aim of this study was to evaluate the healing process in bone defects implanted with hydroxyapatite (HA) or strontium-doped calcium phosphate (SCP) granules, in non-ovariectomised (non-OVX) and ovariectomised (OVX) rats. After 0 (baseline), six and 28d, bone samples were harvested for gene expression analysis, histology and histomorphometry. Tumour necrosis factor-α (TNF-α), at six days, was higher in the HA, in non-OVX and OVX, whereas interleukin-6 (IL-6), at six and 28d, was higher in SCP, but only in non-OVX. Both materials produced a similar expression of the receptor activator of nuclear factor kappa-B ligand (RANKL). Higher expression of osteoclastic markers, calcitonin receptor (CR) and cathepsin K (CatK), were detected in the HA group, irrespective of non-OVX or OVX. The overall bone formation was comparable between HA and SCP, but with topological differences. The bone area was higher in the defect centre of the HA group, mainly in the OVX, and in the defect periphery of the SCP group, in both non-OVX and OVX. It is concluded that HA and SCP granules result in comparable bone formation in trabecular bone defects. As judged by gene expression and histological analyses, the two materials induced different inflammatory and bone remodelling responses. The modulatory effects are associated with differences in the spatial distribution of the newly formed bone.

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    Strontium-doped calcium phosphate and hydroxyapatite granules promote different inflammatory and bone remodelling responses in normal and ovariectomised rats
  • 14.
    Cimenci, Cagla Eren
    et al.
    Univ Ottawa Heart Inst, Canada; Univ Ottawa, Canada.
    Blackburn, Nick J. R.
    Univ Ottawa Heart Inst, Canada; Univ Ottawa, Canada.
    Sedlakova, Veronika
    Univ Ottawa Heart Inst, Canada.
    Pupkaite, Justina
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Univ Ottawa Heart Inst, Canada; Univ Ottawa, Canada.
    Munoz, Marcelo
    Univ Ottawa Heart Inst, Canada.
    Rotstein, Benjamin H.
    Univ Ottawa Heart Inst, Canada; Univ Ottawa, Canada.
    Spiegel, David A.
    Yale Univ, CT 06510 USA.
    Alarcon, Emilio I.
    Univ Ottawa Heart Inst, Canada; Univ Ottawa, Canada.
    Suuronen, Erik J.
    Univ Ottawa Heart Inst, Canada; Univ Ottawa, Canada.
    Combined Methylglyoxal Scavenger and Collagen Hydrogel Therapy Prevents Adverse Remodeling and Improves Cardiac Function Post-Myocardial Infarction2022In: Advanced Functional Materials, ISSN 1616-301X, E-ISSN 1616-3028, Vol. 32, no 1, article id 2108630Article in journal (Refereed)
    Abstract [en]

    Methylglyoxal (MG) is a highly reactive dicarbonyl and the main precursor of advanced glycation end-products (AGEs). After myocardial infarction (MI), MG-derived AGEs accumulate in the heart and contribute to adverse remodeling and loss of cardiac function. In this study, the flavonoid fisetin, a dicarbonyl scavenger, is used to reduce the negative effects of MG in the post-MI heart. A fisetin-loaded collagen type I hydrogel (fisetin-HG) is injected intramyocardially in mice at 3 h post-MI, and compared to fisetin-alone, hydrogel-alone, or saline treatment. Fisetin-HG treatment increases the level of glyoxalase-1 (the main MG-metabolizing enzyme), reduces MG-AGE accumulation, and decreases oxidative stress in the MI heart, which is associated with smaller scar size and improved cardiac function. Treatment with fisetin-HG also promotes neovascularization and increases the number of pro-healing macrophages in the infarct area, while reducing the number of pro-inflammatory macrophages. Taken together, the results demonstrate that the fisetin-collagen hydrogel therapy can reduce the accumulation and negative effects of MG post-MI. This therapy may be a promising approach to limit adverse cardiac remodeling, prevent damage, and preserve function of the infarcted heart.

  • 15.
    Eskilson, Olof
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biophysics and bioengineering. Linköping University, Faculty of Science & Engineering.
    Zattarin, Elisa
    Linköping University, Department of Physics, Chemistry and Biology, Biophysics and bioengineering. Linköping University, Faculty of Science & Engineering.
    Berglund, Linn
    Division of Materials Science, Department of Engineering Sciences and Mathematics, Luleå University of Technology, Luleå, Sweden.
    Oksman, Kristiina
    Division of Materials Science, Department of Engineering Sciences and Mathematics, Luleå University of Technology, Luleå, Sweden.
    Hanna, Kristina
    Linköping University, Department of Biomedical and Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Regionledningskontoret, Center for Disaster Medicine and Traumatology.
    Rakar, Jonathan
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Regionledningskontoret, Center for Disaster Medicine and Traumatology.
    Sivlér, Petter
    Linköping University, Department of Physics, Chemistry and Biology, Biophysics and bioengineering. Linköping University, Faculty of Science & Engineering.
    Skog, Mårten
    Linköping University, Department of Physics, Chemistry and Biology, Biophysics and bioengineering. Linköping University, Faculty of Science & Engineering.
    Rinklake, Ivana
    Linköping University, Department of Biomedical and Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Regionledningskontoret, Center for Disaster Medicine and Traumatology.
    Shamasha, Rozalin
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Regionledningskontoret, Center for Disaster Medicine and Traumatology.
    Sotra, Zeljana
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Regionledningskontoret, Center for Disaster Medicine and Traumatology.
    Starkenberg, Annika
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Regionledningskontoret, Center for Disaster Medicine and Traumatology.
    Odén, Magnus
    Linköping University, Department of Physics, Chemistry and Biology, Nanostructured Materials. Linköping University, Faculty of Science & Engineering.
    Wiman, Emanuel
    Cardiovascular Research Centre, School of Medical Sciences, Örebro University, Örebro, Sweden.
    Khalaf, Hazem
    Cardiovascular Research Centre, School of Medical Sciences, Örebro University, Örebro, Sweden.
    Bengtsson, Torbjörn
    Cardiovascular Research Centre, School of Medical Sciences, Örebro University, Örebro, Sweden.
    Junker, Johan
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Regionledningskontoret, Center for Disaster Medicine and Traumatology.
    Selegård, Robert
    Linköping University, Department of Physics, Chemistry and Biology, Biophysics and bioengineering. Linköping University, Faculty of Science & Engineering.
    Björk, Emma
    Linköping University, Department of Physics, Chemistry and Biology, Nanostructured Materials. Linköping University, Faculty of Science & Engineering.
    Aili, Daniel
    Linköping University, Department of Physics, Chemistry and Biology, Biophysics and bioengineering. Linköping University, Faculty of Science & Engineering.
    Nanocellulose composite wound dressings for real-time pH wound monitoring2023In: Materials Today Bio, ISSN 2590-0064, Vol. 19, article id 100574Article in journal (Refereed)
    Abstract [en]

    The skin is the largest organ of the human body. Wounds disrupt the functions of the skin and can have catastrophic consequences for an individual resulting in significant morbidity and mortality. Wound infections are common and can substantially delay healing and can result in non-healing wounds and sepsis. Early diagnosis and treatment of infection reduce risk of complications and support wound healing. Methods for monitoring of wound pH can facilitate early detection of infection. Here we show a novel strategy for integrating pH sensing capabilities in state-of-the-art hydrogel-based wound dressings fabricated from bacterial nanocellulose (BC). A high surface area material was developed by self-assembly of mesoporous silica nanoparticles (MSNs) in BC. By encapsulating a pH-responsive dye in the MSNs, wound dressings for continuous pH sensing with spatiotemporal resolution were developed. The pH responsive BC-based nanocomposites demonstrated excellent wound dressing properties, with respect to conformability, mechanical properties, and water vapor transmission rate. In addition to facilitating rapid colorimetric assessment of wound pH, this strategy for generating functional BC-MSN nanocomposites can be further be adapted for encapsulation and release of bioactive compounds for treatment of hard-to-heal wounds, enabling development of novel wound care materials.

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  • 16.
    Fursatz, Marian
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
    Skog, Mårten
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering. S2Med AB, Linnegatan 9, SE-58225 Linkoping, Sweden.
    Sivlér, Petter
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, Faculty of Science & Engineering. S2Med AB, Linnegatan 9, SE-58225 Linkoping, Sweden.
    Palm, Eleonor
    Orebro Univ, Sweden.
    Aronsson, Christopher
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
    Skallberg, Andreas
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Surface Physics and Nano Science. Linköping University, Faculty of Science & Engineering.
    Greczynski, Grzegorz
    Linköping University, Department of Physics, Chemistry and Biology, Thin Film Physics. Linköping University, Faculty of Science & Engineering.
    Khalaf, Hazem
    Orebro Univ, Sweden.
    Bengtsson, Torbjorn
    Orebro Univ, Sweden.
    Aili, Daniel
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
    Functionalization of bacterial cellulose wound dressings with the antimicrobial peptide epsilon-poly-L-Lysine2018In: Biomedical Materials, ISSN 1748-6041, E-ISSN 1748-605X, Vol. 13, no 2, article id 025014Article in journal (Refereed)
    Abstract [en]

    Wound dressings based on bacterial cellulose (BC) can form a soft and conformable protective layer that can stimulate wound healing while preventing bacteria from entering the wound. Bacteria already present in the wound can, however, thrive in the moist environment created by the BC dressing which can aggravate the healing process. Possibilities to render the BC antimicrobial without affecting the beneficial structural and mechanical properties of the material would hence be highly attractive. Here we present methods for functionalization of BC with epsilon-poly-L-Lysine (epsilon-PLL), a non-toxic biopolymer with broad-spectrum antimicrobial activity. Low molecular weight epsilon-PLL was crosslinked in pristine BC membranes and to carboxymethyl cellulose functionalized BC using carbodiimide chemistry. The functionalization of BC with epsilon-PLL inhibited growth of S. epidermidis on the membranes but did not affect the cytocompatibility to cultured human fibroblasts as compared to native BC. The functionalization had no significant effects on the nanofibrous structure and mechanical properties of the BC. The possibility to functionalize BC with epsilon-PLL is a promising, green and versatile approach to improve the performance of BC in wound care and other biomedical applications.

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  • 17.
    Gelmi, Amy
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biosensors and Bioelectronics. Linköping University, The Institute of Technology.
    Higgins, Michael
    University of Wollongong, New South Wales, Australia.
    Wallace, Gordon
    University of Wollongong, New South Wales, Australia.
    Rafat, Mehrdad
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Jager, Edwin
    Linköping University, Department of Physics, Chemistry and Biology, Biosensors and Bioelectronics. Linköping University, The Institute of Technology.
    Electroactive Biomaterial Solutions for Tissue Engineering2013Conference paper (Other academic)
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    Electroactive Biomaterials Solutions for Tissue Engineering
  • 18.
    Gelmi, Amy
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biosensors and Bioelectronics. Linköping University, The Institute of Technology.
    Ljunggren, Monika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Rafat, Mehrdad
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Jager, Edwin
    Linköping University, Department of Physics, Chemistry and Biology, Biosensors and Bioelectronics. Linköping University, The Institute of Technology.
    Electroactive scaffolds for cardiac tissue regeneration2013Conference paper (Other academic)
    Abstract [en]

    Myocardial Infarction (MI), commonly known as a heart attack, is the interruption of blood supply to a part of the heart, causing heart cells to die. In order to restore function by-pass surgery or ultimately heart transplantation is needed. However, due to the shortage of organ donors and complications associated with immune suppressive treatments, development of new strategies to help regenerate the injured heart is necessary. Stem cell therapy can be used to repair necrotic heart tissue and achieve myocardial regeneration. This research is focused on developing implantable electroactive fiber scaffolds that will increase the differentiation ratio of mesenchymal stem cells into cardiomyocytes and thus increase the formation of novel cardiac tissue to repair or replace the damaged cardiac tissue after MI. Composite nanofibrous scaffold of poly(dl-lactide-co-glycolide) (PLGA) have been coated with biodoped polypyrrole to create an electroactive fiber scaffold, with controllable fiber dimensions and alignment. The electrical properties of the polymers are an integral factor in creating these 'intelligent' 3-D materials; not only does the inherent conductivity provide a platform for electrical stimulation, but the ionic actuation of the polymer can also provide mechanical stimulation to the seeded cells. The biocompatibility of the polymer, PLGA scaffolds, and coated PLGA scaffolds has been investigated using primary cardiovascular progenitor cells.

  • 19.
    Guex, Anne Geraldine
    et al.
    Imperial Coll London, England.
    Puetzer, Jennifer L.
    Imperial Coll London, England.
    Armgarth, Astrid
    Imperial Coll London, England.
    Littmann, Elena
    Imperial Coll London, England.
    Stavrinidou, Eleni
    Linköping University, Department of Science and Technology, Physics and Electronics. Linköping University, Faculty of Science & Engineering. Imperial Coll London, England.
    Giannelis, Emmanuel P.
    Cornell University, NY 14853 USA.
    Malliaras, George G.
    Ecole National Super Mines, France.
    Stevens, Molly M.
    Imperial Coll London, England.
    Highly porous scaffolds of PEDOT:PSS for bone tissue engineering2017In: Acta Biomaterialia, ISSN 1742-7061, E-ISSN 1878-7568, Vol. 62, p. 91-101Article in journal (Refereed)
    Abstract [en]

    Conjugated polymers have been increasingly considered for the design of conductive materials in the field of regenerative medicine. However, optimal scaffold properties addressing the complexity of the desired tissue still need to be developed. The focus of this study lies in the development and evaluation of a conductive scaffold for bone tissue engineering. In this study PEDOT:PSS scaffolds were designed and evaluated in vitro using MC3T3-E1 osteogenic precursor cells, and the cells were assessed for distinct differentiation stages and the expression of an osteogenic phenotype. Ice-templated PEDOT:PSS scaffolds presented high pore interconnectivity with a median pore diameter of 53.6 +/- 5.9 mu m and a total pore surface area of 7.72 +/- 1.7 m(2).g(-1). The electrical conductivity, based on I-V curves, was measured to be 140 mu S.cm(-1) with a reduced, but stable conductivity of 6.1 mu S.cm(-1) after 28 days in cell culture media. MC3T3-E1 gene expression levels of ALPL, COL1A1 and RUNX2 were significantly enhanced after 4 weeks, in line with increased extracellular matrix mineralisation, and osteocalcin deposition. These results demonstrate that a porous material, based purely on PEDOT:PSS, is suitable as a scaffold for bone tissue engineering and thus represents a promising candidate for regenerative medicine. Statement of Significance Tissue engineering approaches have been increasingly considered for the repair of non-union fractions, craniofacial reconstruction or large bone defect replacements. The design of complex biomaterials and successful engineering of 3-dimensional tissue constructs is of paramount importance to meet this clinical need. Conductive scaffolds, based on conjugated polymers, present interesting candidates to address the piezoelectric properties of bone tissue and to induce enhanced osteogenesis upon implantation. However, conductive scaffolds have not been investigated in vitro in great measure. To this end, we have developed a highly porous, electrically conductive scaffold based on PEDOT:PSS, and provide evidence that this purely synthetic material is a promising candidate for bone tissue engineering. (C) 2017 Acta Materialia Inc. Published by Elsevier Ltd.

  • 20.
    Haagdorens, Michel
    et al.
    Univ Antwerp, Belgium; Antwerp Univ Hosp, Belgium.
    Edin, Elle
    Univ Montreal, Canada; Univ Montreal, Canada; Maisonneuve Rosemt Hosp Res Ctr, Canada; CHUM Res Ctr, Canada.
    Fagerholm, Per
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Sensory Organs and Communication. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Groleau, Marc
    Maisonneuve Rosemt Hosp Res Ctr, Canada; CHUM Res Ctr, Canada.
    Shtein, Zvi
    Robert H Smith Fac Agr Food & Environm, Israel; Hebrew Univ Jerusalem, Israel.
    Ulcinas, Arturas
    Ctr Phys Sci & Technol, Lithuania.
    Yaari, Amit
    Robert H Smith Fac Agr Food & Environm, Israel; Hebrew Univ Jerusalem, Israel.
    Samanta, Ayan
    Angstrom Lab, Sweden.
    Cepla, Vytautas
    Ctr Phys Sci & Technol, Lithuania; Ferentis UAB, Lithuania.
    Liszka, Aneta
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology.
    Tassignon, Marie-Jose
    Univ Antwerp, Belgium; Antwerp Univ Hosp, Belgium.
    Simpson, Fiona
    Univ Montreal, Canada; Univ Montreal, Canada; Maisonneuve Rosemt Hosp Res Ctr, Canada; CHUM Res Ctr, Canada.
    Shoseyov, Oded
    Robert H Smith Fac Agr Food & Environm, Israel; Hebrew Univ Jerusalem, Israel; CollPlant Ltd, Israel.
    Valiokas, Ramunas
    Ctr Phys Sci & Technol, Lithuania.
    Pintelon, Isabel
    Antwerp Univ, Belgium.
    Kozak Ljunggren, Monika
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Biomedical and Clinical Sciences.
    Griffith, May
    Univ Montreal, Canada; Univ Montreal, Canada; Maisonneuve Rosemt Hosp Res Ctr, Canada; CHUM Res Ctr, Canada.
    Plant Recombinant Human Collagen Type I Hydrogels for Corneal Regeneration2022In: Regenerative Engineering and Translational Medicine, ISSN 2364-4133, Vol. 8, no 2, p. 269-283Article in journal (Refereed)
    Abstract [en]

    Purpose To determine feasibility of plant-derived recombinant human collagen type I (RHCI) for use in corneal regenerative implants Methods RHCI was crosslinked with 1-ethyl-3-(3-dimethyl aminopropyl) carbodiimide (EDC) and N-hydroxysuccinimide (NHS) to form hydrogels. Application of shear force to liquid crystalline RHCI aligned the collagen fibrils. Both aligned and random hydrogels were evaluated for mechanical and optical properties, as well as in vitro biocompatibility. Further evaluation was performed in vivo by subcutaneous implantation in rats and corneal implantation in Gottingen minipigs. Results Spontaneous crosslinking of randomly aligned RHCI (rRHCI) formed robust, transparent hydrogels that were sufficient for implantation. Aligning the RHCI (aRHCI) resulted in thicker collagen fibrils forming an opaque hydrogel with insufficient transverse mechanical strength for surgical manipulation. rRHCI showed minimal inflammation when implanted subcutaneously in rats. The corneal implants in minipigs showed that rRHCI hydrogels promoted regeneration of corneal epithelium, stroma, and nerves; some myofibroblasts were seen in the regenerated neo-corneas. Conclusion Plant-derived RHCI was used to fabricate a hydrogel that is transparent, mechanically stable, and biocompatible when grafted as corneal implants in minipigs. Plant-derived collagen is determined to be a safe alternative to allografts, animal collagens, or yeast-derived recombinant human collagen for tissue engineering applications. The main advantage is that unlike donor corneas or yeast-produced collagen, the RHCI supply is potentially unlimited due to the high yields of this production method. Lay Summary A severe shortage of human-donor corneas for transplantation has led scientists to develop synthetic alternatives. Here, recombinant human collagen type I made of tobacco plants through genetic engineering was tested for use in making corneal implants. We made strong, transparent hydrogels that were tested by implanting subcutaneously in rats and in the corneas of minipigs. We showed that the plant collagen was biocompatible and was able to stably regenerate the corneas of minipigs comparable to yeast-produced recombinant collagen that we previously tested in clinical trials. The advantage of the plant collagen is that the supply is potentially limitless.

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  • 21. Order onlineBuy this publication >>
    Halling Linder, Cecilia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Biochemical and functional properties of mammalian bone alkaline phosphatase isoforms during osteogenesis2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The human skeleton is a living and dynamic tissue that constantly is being renewed in a process called bone remodeling. Old bone is resorbed by osteoclasts and new bone is formed by osteoblasts. Bone is a composite material made up by mineral crystals in the form of hydroxyapatite (calcium and phosphate) that provides the hardness of bone, and collagen fibrils that provides elasticity and flexibility. Alkaline phosphatase (ALP) is a family of enzymes that is present in most species and catalyzes the hydrolysis of various phosphomonoesters at alkaline pH. Despite the generalized use of ALP as a biochemical marker of bone formation, the precise function of bone ALP (BALP) is only now becoming clear. Three circulating human BALP isoforms (B1, B2, and B/I) can be distinguished in healthy individuals and a fourth isoform (B1x) has been discovered in patients with chronic kidney disease and in bone tissue.

    Paper I. Three endogenous phosphocompounds, (i.e., inorganic pyrophosphate (PPi), pyridoxal 5′-phosphate (PLP) and phosphoethanolamine (PEA)), have been suggested to serve as  physiological substrates for BALP. The BALP isoforms display different catalytic properties towards PPi and PLP, which is attributed to their distinct N-linked glycosylation patterns. The catalytic activity, using PEA as substrate, was barely detectable for all BALP isoforms indicating that PEA is not a physiological substrate for BALP.

    Paper II. Mouse serum ALP is frequently measured and interpreted in mammalian bone research. However, little is known about the circulating ALPs in mice and their relation to human ALP. We characterized the circulating and tissue-derived mouse ALP isozymes and isoforms from mixed strains of wild-type and knockout mice. All four BALP isoforms (B/I, B1x, B1, and B2) were identified in mouse serum and bone tissues, in good correspondence with those found in human bones. All mouse tissues, except liver, contained significant ALP activities. This is a notable difference as human liver contains vast amounts of ALP.

    Paper III. The objective of this study was to investigate the binding properties of human collagen type I to human BALP, including the two BALP isoforms B1 and B2, together with ALP from human liver, human placenta and E. coli. A surface plasmon resonance-based analysis showed that BALP binds stronger to collagen type I in comparison with ALPs expressed in non-mineralizing tissues. The B2 isoform binds significantly stronger to collagen type I in comparison with the B1 isoform, indicating that glycosylation differences in human ALPs are of crucial importance for protein–protein interactions with collagen type I.

    Paper IV. Tartrate-resistant acid phosphatase (TRAP) is highly expressed in osteoclasts and frequently used as a marker of bone resorption. Intriguingly, recent studies show that TRAP is also expressed in osteoblasts and osteocytes. TRAP displays enzymatic activity towards the endogenous substrates for BALP, i.e., PPi and PLP. Both TRAP and BALP can alleviate the inhibitory effect of osteopontin on mineralization by dephosphorylation, which suggests a novel role for TRAP in skeletal mineralization.

    List of papers
    1. Glycosylation differences contribute to distinct catalytic properties among bone alkaline phosphatase isoforms.
    Open this publication in new window or tab >>Glycosylation differences contribute to distinct catalytic properties among bone alkaline phosphatase isoforms.
    2009 (English)In: Bone, ISSN 1873-2763, Vol. 45, no 5, p. 987-993Article in journal (Refereed) Published
    Abstract [en]

    Three circulating human bone alkaline phosphatase (BALP) isoforms (B1, B2, and B/I) can be distinguished in healthy individuals and a fourth isoform (B1x) has been discovered in patients with chronic kidney disease and in bone tissue. The present study was designed to correlate differing glycosylation patterns of each BALP isoform with their catalytic activity towards presumptive physiological substrates and to compare those properties with two recombinant isoforms of the tissue-nonspecific ALP (TNALP) isozyme, i.e., TNALP-flag, used extensively for mutation analysis of hypophosphatasia mutations and sALP-FcD(10), a chimeric enzyme recently used as therapeutic drug in a mouse model of infantile hypophosphatasia. The BALP isoforms were prepared from human osteosarcoma (SaOS-2) cells and the kinetic properties were evaluated using the synthetic substrate p-nitrophenylphosphate (pNPP) at pH 7.4 and 9.8, and the three suggested endogenous physiological substrates, i.e., inorganic pyrophosphate (PP(i)), pyridoxal 5'-phosphate (PLP), and phosphoethanolamine (PEA) at pH 7.4. Qualitative glycosylation differences were also assessed by lectin binding and precipitation. The k(cat)/K(M) was higher for B2 for all the investigated substrates. The catalytic activity towards PEA was essentially undetectable. The kinetic activity for TNALP-flag and sALP-FcD(10) was similar to the activity of the human BALP isoforms. The BALP isoforms differed in their lectin binding properties and dose-dependent lectin precipitation, which also demonstrated differences between native and denatured BALP isoforms. The observed differences in lectin specificity were attributed to N-linked carbohydrates. In conclusion, we demonstrate significantly different catalytic properties among the BALP isoforms due to structural differences in posttranslational glycosylation. Our data also suggests that PEA is not an endogenous substrate for the BALP isoforms or for the recombinant TNALP isoforms. The TNALP-flag and the sALP-FcD(10) isoforms faithfully mimic the biological properties of the human BALP isoforms in vivo validating the use of these recombinant enzymes in studies aimed at dissecting the pathophysiology and treating hypophosphatasia.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-21351 (URN)10.1016/j.bone.2009.07.009 (DOI)19631305 (PubMedID)
    Available from: 2009-10-01 Created: 2009-10-01 Last updated: 2016-04-14
    2. Isozyme profile and tissue-origin of alkaline phosphatases in mouse serum
    Open this publication in new window or tab >>Isozyme profile and tissue-origin of alkaline phosphatases in mouse serum
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    2013 (English)In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 53, no 2, p. 399-408Article in journal (Refereed) Published
    Abstract [en]

    Mouse serum alkaline phosphatase (ALP) is frequently measured and interpreted in mammalian bone research. However, little is known about the circulating ALPs in mice and their relation to human ALP isozymes and isoforms. Mouse ALP was extracted from liver, kidney, intestine, and bone from vertebra, femur and calvaria tissues. Serum from mixed strains of wild-type (WT) mice and from individual ALP knockout strains were investigated, i.e., Alpl(-/-) (a.k.a. Akp2 encoding tissue-nonspecific ALP or TNALP), Akp3(-/-) (encoding duodenum-specific intestinal ALP or dIALP), and Alpi(-/-) (a.k.a. Akp6 encoding global intestinal ALP or gIALP). The ALP isozymes and isoforms were identified by various techniques and quantified by high-performance liquid chromatography. Results from the WT and knockout mouse models revealed identical bone-specific ALP isoforms (B/I. B1, and B2) as found in human serum, but in addition mouse serum contains the B1x isoform only detected earlier in patients with chronic kidney disease and in human bone tissue. The two murine intestinal isozymes, dIALP and gIALP, were also identified in mouse serum. All four bone-specific ALP isoforms (B/I, B1x, B1, and B2) were identified in mouse bones, in good correspondence with those found in human bones. All mouse tissues, except liver and colon, contained significant ALP activities. This is a notable difference as human liver contains vast amounts of ALP. Histochemical staining, Northern and Western blot analyses confirmed undetectable ALP expression in liver tissue. ALP activity staining showed some positive staining in the bile canaliculi for BALB/c and FVB/N WT mice, but not in C57BI/6 and ICR mice. Taken together, while the main source of ALP in human serum originates from bone and liver, and a small fraction from intestine (andlt;5%), mouse serum consists mostly of bone ALP, including all four isoforms, B/I, B1x, B1, and B2, and two intestinal ALP isozymes dIALP and gIALR We suggest that the genetic nomenclature for the Alpl gene in mice (i.e., ALP liver) should be reconsidered since murine liver has undetectable amounts of ALP activity. These findings should pave the way for the development of user-friendly assays measuring circulating bone-specific ALP in mouse models used in bone and mineral research.

    Place, publisher, year, edition, pages
    Elsevier, 2013
    Keywords
    Alkaline phosphatase, Bone, Glycosylation, Hypophosphatasia, Knockout mice, Mineralization
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-90744 (URN)10.1016/j.bone.2012.12.048 (DOI)000315763700010 ()
    Note

    Funding Agencies|County Council of Ostergotland in Sweden||National Institutes of Health, USA|DE012889|

    Available from: 2013-04-05 Created: 2013-04-05 Last updated: 2017-12-06
    3. Glycation Contributes to Interaction Between Human Bone Alkaline Phosphatase and Collagen Type I
    Open this publication in new window or tab >>Glycation Contributes to Interaction Between Human Bone Alkaline Phosphatase and Collagen Type I
    2016 (English)In: Calcified Tissue International, ISSN 0171-967X, E-ISSN 1432-0827, Vol. 98, no 3, p. 284-293Article in journal (Refereed) Published
    Abstract [en]

    Bone is a biological composite material comprised primarily of collagen type I and mineral crystals of calcium and phosphate in the form of hydroxyapatite (HA), which together provide its mechanical properties. Bone alkaline phosphatase (ALP), produced by osteoblasts, plays a pivotal role in the mineralization process. Affinity contacts between collagen, mainly type II, and the crown domain of various ALP isozymes were reported in a few in vitro studies in the 1980s and 1990s, but have not attracted much attention since, although such interactions may have important implications for the bone mineralization process. The objective of this study was to investigate the binding properties of human collagen type I to human bone ALP, including the two bone ALP isoforms B1 and B2. ALP from human liver, human placenta and E. coli were also studied. A surface plasmon resonance-based analysis, supported by electrophoresis and blotting, showed that bone ALP binds stronger to collagen type I in comparison with ALPs expressed in non-mineralizing tissues. Further, the B2 isoform binds significantly stronger to collagen type I in comparison with the B1 isoform. Human bone and liver ALP (with identical amino acid composition) displayed pronounced differences in binding, revealing that post-translational glycosylation properties govern these interactions to a large extent. In conclusion, this study presents the first evidence that glycosylation differences in human ALPs are of crucial importance for protein–protein interactions with collagen type I, although the presence of the ALP crown domain may also be necessary. Different binding affinities among the bone ALP isoforms may influence the mineral-collagen interface, mineralization kinetics, and degree of bone matrix mineralization, which are important factors determining the material properties of bone.

    Place, publisher, year, edition, pages
    Springer-Verlag New York, 2016
    Keywords
    Alkaline phosphatase; Bone; Collagen; Glycosylation; Mineralization; Surface plasmon resonance
    National Category
    Endocrinology and Diabetes Dentistry
    Identifiers
    urn:nbn:se:liu:diva-127099 (URN)10.1007/s00223-015-0088-0 (DOI)000373744700008 ()26645431 (PubMedID)
    Note

    Funding agencies:  Region Ostergotland, Sweden

    Available from: 2016-04-14 Created: 2016-04-14 Last updated: 2017-11-30Bibliographically approved
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  • 22. Order onlineBuy this publication >>
    Hammerman, Malin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Tendon Healing: Mechanical Loading, Microdamage and Gene Expression2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Mechanical loading and the inflammatory response during tendon healing might be important for the healing process. Mechanical loading can improve the healing tendon but the mechanism is not fully understood. The aim of this thesis was to further clarify the effect of mechanical loading on tendon healing and how mechanical loading affects the inflammatory response during the healing process.

    We used a rat Achilles tendon model to study healing. The rats were exposed to different degrees of loading by unloading methods such as paralysis of the calf muscles with Botox, tail suspension, and an orthosis (a boot). Full loading was achieved by free cage activity or treadmill walking. Microdamage in tendons, unloaded with Botox, was also investigated by needling. The healing tendons were evaluated in a materials testing machine (to analyze the mechanical properties), by gene expression analysis (microarray and PCR), or histology.

    Our results show that moderate loading (unloading with Botox) improves the mechanical properties of healing tendons compared to minimal loading (unloading with Botox in combination with tail suspension or a boot), especially the material properties. In accordance to these findings, expression of extracellular matrix genes were also increased by moderate compared to minimal loading.

    Full loading improved all mechanical properties and the expression of extracellular matrix genes was further increased compared to moderate loading. However, structural properties, such as the strength and the size of the healing tendon, were more affected by full loading. Full loading also affected the expression of inflammation-related genes during the early healing phase, 3 and 5 days after tendon injury, and increased the number of immune cells in the healing tendon tissue. Also microdamage of the healing tendon (detected by blood leakage) was increased by full loading compared to moderate loading during the early healing phase.

    Induced microdamage by repeated needling in the healing tendon tissue increased the structural properties of the healing tendon. The gene expression after needling was similar to the gene expression after full loading.

    The improvement of mechanical properties by loading in healing tendons was decreased by an anti-inflammatory drug called parecoxib, which decreases the production of prostaglandins by inhibiting COX-2 activity. The effect of parecoxib was reduced when loading was reduced but we could not confirm that the effect of parecoxib was related to the degree of loading. However, parecoxib abolished the stimulatory effect of microdamage.

    In conclusion, these studies show that moderate loading improves the quality of the healing tendon whereas full loading also increases the quantity of the healing tendon tissue. Full loading creates microdamage and increases inflammation during the early healing phase. The strong effect of full loading on the structural properties might be due to microdamage. Indeed, the anti-inflammatory drug parecoxib seems to impair mechanical stimulation of healing tendons by reducing the response to microdamage.

    List of papers
    1. Low-level mechanical stimulation is sufficient to improve tendon healing in rats
    Open this publication in new window or tab >>Low-level mechanical stimulation is sufficient to improve tendon healing in rats
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    2012 (English)In: Journal of applied physiology, ISSN 8750-7587, E-ISSN 1522-1601, Vol. 113, no 9, p. 1398-1402Article in journal (Refereed) Published
    Abstract [en]

    Treatment of tendon injuries often involves immobilization. However, immobilization might not prevent mild involuntary isometric muscle contraction. The effect of weak forces on tendon healing is therefore of clinical interest. Studies of tendon healing with various methods for load reduction in rat Achilles tendon models show a consistent reduction in tendon strength by at least half, compared with voluntary cage activity. Unloading was not complete in any of these models, and the healing tendon was therefore still exposed to mild mechanical stimulation. By reducing the forces acting on the tendon even further, we now studied the effects of this mild stimulation. Rat Achilles tendons were transected and allowed to heal spontaneously under four different loading conditions: 1) normal cage activity; 2) calf muscle paralysis induced by botulinum toxin A (Botox); 3) tail suspension; 4) Botox and tail suspension, combined, to eliminate even mild stimulation. Healing was evaluated by mechanical testing after 8 days. Botox alone and suspension alone both reduced tendon callus size (transverse area), thereby impairing its strength compared with normal cage activity. The combination of Botox and suspension did not further reduce tendon callus size but drastically impaired the material properties of the tendon callus compared with each treatment alone. The peak force was only a fifth of that in the normal cage activity group. The results indicate that also the mild loading that occurs with either Botox or suspension alone stimulates tendon healing. This stimulation appears to affect mainly tissue quality, whereas stronger stimulation also increases callus size.

    Place, publisher, year, edition, pages
    American Physiological Society, 2012
    Keywords
    Achilles tendon, mechanical stress, wound healing, hindlimb unloading, immobilization
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-85847 (URN)10.1152/japplphysiol.00491.2012 (DOI)000310649200007 ()
    Note

    Funding Agencies|Swedish Research Council|2009-6725|Linkoping University||Ostergotland County Council||King Gustaf V and Queen Victoria Free Mason Foundation||Swedish National Center for Research in Sports||

    Available from: 2012-11-30 Created: 2012-11-30 Last updated: 2018-02-20
    2. Different gene response to mechanical loading during early and late phases of rat Achilles tendon healing
    Open this publication in new window or tab >>Different gene response to mechanical loading during early and late phases of rat Achilles tendon healing
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    2017 (English)In: Journal of applied physiology, ISSN 8750-7587, E-ISSN 1522-1601, Vol. 123, no 4, p. 800-815Article in journal (Refereed) Published
    Abstract [en]

    Mechanical loading stimulates tendon healing both when applied in the inflammatory phase and in the early remodeling phase of the process, although not necessarily via the same mechanisms. We investigated the gene response to mechanical loading in these two phases of tendon healing. The right Achilles tendon in rats was transected, and the hindlimbs were unloaded by tail suspension. The rats were exposed to 5 min of treadmill running 3 or 14 days after tendon transection. Thereafter, they were resuspended for 15 min or 3 h until euthanasia. The controls were suspended continuously. Gene analysis was first performed by microarray analysis followed by quantitative RTPCR on selected genes, focusing on inflammation. Fifteen minutes after loading, the most important genes seemed to be the transcription factors EGR1 and C-FOS, regardless of healing phase. These transcription factors might promote tendon cell proliferation and differentiation, stimulate collagen production, and regulate inflammation. Three hours after loading on day 3, inflammation was strongly affected. Seven inflammation-related genes were upregulated according to PCR: CCL20, CCL7, IL-6, NFIL3, PTX3, SOCS1, and TLR2. These genes can be connected to macrophages, T cells, and recruitment of leukocytes. According to Ingenuity Pathway Analysis, the recruitment of leukocytes was increased by loading on day 3, which also was confirmed by histology. This inflammation-related gene response was not seen on day 14. Our results suggest that the immediate gene response after mechanical loading is similar in the early and late phases of healing but the late gene response is different. NEW amp; NOTEWORTHY This study investigates the direct effect of mechanical loading on gene expression during different healing phases in tendon healing. One isolated episode of mechanical loading was studied in otherwise unloaded healing tendons. This enabled us to study a time sequence, i.e., which genes were the first ones to be regulated after the loading episode.

    Place, publisher, year, edition, pages
    AMER PHYSIOLOGICAL SOC, 2017
    Keywords
    tendon healing; gene expression; inflammation; mechanical loading
    National Category
    Microbiology
    Identifiers
    urn:nbn:se:liu:diva-143094 (URN)10.1152/japplphysiol.00323.2017 (DOI)000414037800002 ()28705996 (PubMedID)
    Note

    Funding Agencies|Swedish Research Council [K2013-52X-02031-47-5]; Swedish National Centre for Research in Sports

    Available from: 2017-11-22 Created: 2017-11-22 Last updated: 2018-04-03
    3. Microtrauma stimulates rat Achilles tendon healing via an early gene expression pattern similar to mechanical loading
    Open this publication in new window or tab >>Microtrauma stimulates rat Achilles tendon healing via an early gene expression pattern similar to mechanical loading
    2014 (English)In: Journal of applied physiology, ISSN 8750-7587, E-ISSN 1522-1601, Vol. 116, no 1, p. 54-60Article in journal (Refereed) Published
    Abstract [en]

    Mechanical loading increases the strength of healing tendons, but also induces small localized bleedings. Therefore, it is unclear if increased strength after loading is a response to mechanotransduction or microtrauma. We have previously found only five genes to be up-regulated 15 min after a single loading episode, of them four were transcription factors. These genes are followed by hundreds of genes after 3 h, many of them involved in inflammation. We now compared healing in mechanically unloaded tendons with or without added microtrauma induced by needling of the healing tissue. Nineteen rats received Botox into the calf muscle to reduce loading, and the Achilles tendon was transected. Ten rats were randomized to needling days 2-5. Mechanical testing on day 8 showed increased strength by 45% in the needling group. Next, another 24 rats were similarly unloaded, and 16 randomized to needling on day 5 after transection. Nineteen characteristic genes, known to be regulated by loading in this model, were analyzed by qRT-PCR. Four of these genes were regulated 15 min after needling. Three of them (Egr1, c-Fos, Rgs1) were among the five regulated genes after loading in a previous study. Sixteen of the 19 genes were regulated after 3 h, in the same way as after loading. In conclusion, needling increased strength, and there was a striking similarity between the gene expression response to needling and mechanical loading. This suggests that the response to loading in early tendon healing can, at least in part, be a response to microtrauma.

    Place, publisher, year, edition, pages
    American Physiological Society, 2014
    Keywords
    qRT-PCR; unloading; mechanical testing; early response genes; inflammation
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-103870 (URN)10.1152/japplphysiol.00741.2013 (DOI)000329196100008 ()
    Available from: 2014-01-31 Created: 2014-01-30 Last updated: 2018-02-20
    4. COX-2 inhibition impairs mechanical stimulation of early tendon healing in rats by reducing the response to microdamage
    Open this publication in new window or tab >>COX-2 inhibition impairs mechanical stimulation of early tendon healing in rats by reducing the response to microdamage
    2015 (English)In: Journal of applied physiology, ISSN 8750-7587, E-ISSN 1522-1601, Vol. 119, no 5, p. 534-540Article in journal (Refereed) Published
    Abstract [en]

    Early tendon healing can be stimulated by mechanical loading and inhibited by cyclooxygenase (COX) inhibitors (nonsteroidal anti-inflammatory drugs). Therefore, we investigated if impairment of tendon healing by a COX-2 inhibitor (parecoxib) is related to loading. Because loading might infer microdamage, which also stimulates healing, we also investigated if this effect is inhibited by parecoxib. The Achilles tendon was transected in 114 rats. Three degrees of loading were used: full loading, partial unloading, and unloading (no unloading, Botox injections in the plantar flexor muscles, or Botox in combination with tail suspension). For each loading condition, the rats received either parecoxib or saline. In a second experiment, rats were unloaded with Botox, and the tendon was subjected to microdamage by needling combined with either saline or parecoxib. Mechanical testing day 7 showed that there was a significant interaction between loading and parecoxib for peak force at failure (P less than 0.01). However, logarithmic values showed no significant interaction, meaning that we could not exclude that the inhibitory effect of parecoxib was proportionate to the degree of loading. Microbleeding was common in the healing tissue, suggesting that loading caused microdamage. Needling increased peak force at failure (P less than 0.01), and this effect of microdamage was almost abolished by parecoxib (P less than 0.01). Taken together, this suggests that COX-2 inhibition impairs the positive effects of mechanical loading during tendon healing, mainly by reducing the response to microdamage.

    Place, publisher, year, edition, pages
    AMER PHYSIOLOGICAL SOC, 2015
    Keywords
    tendon healing; COX-2; NSAIDs; mechanical stimulation; microdamage
    National Category
    Physiology Pharmacology and Toxicology
    Identifiers
    urn:nbn:se:liu:diva-122063 (URN)10.1152/japplphysiol.00239.2015 (DOI)000360694300013 ()26159755 (PubMedID)
    Note

    Funding Agencies|Swedish Research Council [K2013-52X-02031-47-5]; Swedish National Centre for Research in Sports; King Gustaf V and Queen Victoria Free Mason Foundation

    Available from: 2015-12-18 Created: 2015-10-19 Last updated: 2019-02-11
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    Tendon Healing: Mechanical Loading, Microdamage and Gene Expression
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  • 23.
    Hayes, Sally
    et al.
    Cardiff University, Wales; Cardiff University, Wales.
    Lewis, Phillip
    Cardiff University, Wales; Cardiff University, Wales.
    Islam, Mohammad Mirazul
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Institute, Sweden.
    Doutch, James
    Diamond Light Source, England.
    Sorensen, Thomas
    Diamond Light Source, England.
    White, Tomas
    Cardiff University, Wales; Cardiff University, Wales.
    Griffith, May
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Institute, Sweden.
    Meek, Keith M.
    Cardiff University, Wales; Cardiff University, Wales.
    The structural and optical properties of type III human collagen biosynthetic corneal substitutes2015In: Acta Biomaterialia, ISSN 1742-7061, E-ISSN 1878-7568, Vol. 25, p. 121-130Article in journal (Refereed)
    Abstract [en]

    The structural and optical properties of clinically biocompatible, cell-free hydrogels comprised of synthetically cross-linked and moulded recombinant human collagen type III (RHCIII) with and without the incorporation of 2-methacryloyloxyethyl phosphorylcholine (MPC) were assessed using transmission electron microscopy (TEM), X-ray scattering, spectroscopy and refractometry. These findings were examined alongside similarly obtained data from 21 human donor corneas. TEM demonstrated the presence of loosely bundled aggregates of fine collagen filaments within both RHCIII and RHCIII-MPC implants, which X-ray scattering showed to lack D-banding and be preferentially aligned in a uniaxial orientation throughout. This arrangement differs from the predominantly biaxial alignment of collagen fibrils that exists in the human cornea. By virtue of their high water content (90%), very fine collagen filaments (2-9 nm) and lack of cells, the collagen hydrogels were found to transmit almost all incident light in the visible spectrum. They also transmitted a large proportion of UV light compared to the cornea which acts as an effective UV filter. Patients implanted with these hydrogels should be cautious about UV exposure prior to regrowth of the epithelium and in-growth of corneal cells into the implants. (C) 2015 Acta Materialia Inc. Published by Elsevier Ltd.

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  • 24.
    Iandolo, Donata
    et al.
    Linköping University, Department of Science and Technology, Physics and Electronics. Linköping University, Faculty of Science & Engineering.
    Ravichandran, Akhilandeshwari
    School of Chemical and Biomedical Engineering, Nanyang Technological University, Singapore.
    Liu, Xianjie
    Linköping University, Department of Physics, Chemistry and Biology, Surface Physics and Chemistry. Linköping University, Faculty of Science & Engineering.
    Wen, Feng
    School of Chemical and Biomedical Engineering, Nanyang Technological University, Singapore.
    Chan, Jerry K Y
    Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
    Berggren, Magnus
    Linköping University, Department of Science and Technology, Physics and Electronics. Linköping University, Faculty of Science & Engineering.
    Teoh, Swee-Hin
    School of Chemical and Biomedical Engineering, Nanyang Technological University, Singapore.
    Simon, Daniel T
    Linköping University, Department of Science and Technology, Physics and Electronics. Linköping University, Faculty of Science & Engineering.
    Development and Characterization of Organic Electronic Scaffolds for Bone Tissue Engineering2016In: Advanced Healthcare Materials, ISSN 2192-2640, E-ISSN 2192-2659, Vol. 5, no 12, p. 1505-1512Article in journal (Refereed)
    Abstract [en]

    Bones have been shown to exhibit piezoelectric properties, generating electrical potential upon mechanical deformation and responding to electrical stimulation with the generation of mechanical stress. Thus, the effects of electrical stimulation on bone tissue engineering have been extensively studied. However, in bone regeneration applications, only few studies have focused on the use of electroactive 3D biodegradable scaffolds at the interphase with stem cells. Here a method is described to combine the bone regeneration capabilities of 3D-printed macroporous medical grade polycaprolactone (PCL) scaffolds with the electrical and electrochemical capabilities of the conducting polymer poly(3,4-ethylenedioxythiophene) (PEDOT). PCL scaffolds have been highly effective in vivo as bone regeneration grafts, and PEDOT is a leading material in the field of organic bioelectronics, due to its stability, conformability, and biocompatibility. A protocol is reported for scaffolds functionalization with PEDOT, using vapor-phase polymerization, resulting in a conformal conducting layer. Scaffolds' porosity and mechanical stability, important for in vivo bone regeneration applications, are retained. Human fetal mesenchymal stem cells proliferation is assessed on the functionalized scaffolds, showing the cytocompatibility of the polymeric coating. Altogether, these results show the feasibility of the proposed approach to obtain electroactive scaffolds for electrical stimulation of stem cells for regenerative medicine.

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  • 25.
    Jangamreddy, Jaganmohan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. LV Prasad Eye Inst, India.
    Haagdorens, Michel K. C.
    Antwerp Univ Hosp, Belgium; Univ Antwerp, Belgium.
    Mirazul Islam, Mohammad Mirazul
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Lewis, Philip
    Cardiff Univ, Wales.
    Samanta, Ayan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Fagerholm, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Liszka, Aneta
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Kozak Ljunggren, Monika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Buznyk, Oleksiy
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Alarcon, Emilio I.
    Univ Ottawa, Canada.
    Zakaria, Nadia
    Antwerp Univ Hosp, Belgium; Univ Antwerp, Belgium.
    Meek, Keith M.
    Cardiff Univ, Wales.
    Griffith, May
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Univ Montreal, Canada; Univ Montreal, Canada.
    Short peptide analogs as alternatives to collagen in pro-regenerative corneal implants2018In: Acta Biomaterialia, ISSN 1742-7061, E-ISSN 1878-7568, Vol. 69, p. 120-130Article in journal (Refereed)
    Abstract [en]

    Short collagen-like peptides (CLPs) are being proposed as alternatives to full-length collagen for use in tissue engineering, on their own as soft hydrogels, or conjugated to synthetic polymer for mechanical strength. However, despite intended clinical use, little is known about their safety and efficacy, mechanism of action or degree of similarity to the full-length counterparts they mimic. Here, we show the functional equivalence of a CLP conjugated to polyethylene glycol (CLP-PEG) to full-length recombinant human collagen in vitro and in promoting stable regeneration of corneal tissue and nerves in a pre- clinicalmini-pig model. We also show that these peptide analogs exerted their pro-regeneration effects through stimulating extracellular vesicle production by host cells. Our results support future use of CLP-PEG implants for corneal regeneration, suggesting the feasibility of these or similar peptide analogs in clinical application in the eye and other tissues. Statement of significance Although biomaterials comprising full-length recombinant human collagen and extracted animal collagen have been evaluated and used clinically, these macromolecules provide only a limited number of functional groups amenable to chemical modification or crosslinking and are demanding to process. Synthetic, customizable analogs that are functionally equivalent, and can be readily scaled-up are therefore very desirable for pre-clinical to clinical translation. Here, we demonstrate, using cornea regeneration as our test bed, that collagen-like-peptides conjugated to multifunctional polyethylene glycol (CLP-PEG) when grafted into mini-pigs as corneal implants were functionally equivalent to recombinant human collagen-based implants that were successfully tested in patients. We also show for the first time that these materials affected regeneration through stimulation of extracellular vesicle production by endogenous host cells that have migrated into the CLP-PEG scaffolds. (C) 2018 Acta Materialia Inc. Published by Elsevier Ltd.

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  • 26.
    Johansson, Patrik
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Characterization of Protein Surface Interactions: Collagen and Osteocalcin2013Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    This work investigates how the proteins collagen type I and human osteocalcin interact with various surfaces. A pH-series of collagen adsorbed onto methyl terminated self-assembled monolayers has been made and the results indicate that less tropocollagen is found on the surfaces at pH below 6.0 and that biofilms made of larger fibrils with a more ordered 3D-structure are formed at pH 6.0 and above. This work also shows that it is possible to divide the amide I region of a vibrational Sum Frequency Generation (v-SFG) spectra into three peaks. These peaks can be correlated to the three amino acid residues glycine, proline and hydroxyproline, which have a high abundance in collagen. Analysis of different polarization combinations probing chiral and achiral contributions demonstrates that glycine has a higher contribution over proline and hydroxyproline in achiral responses, whereas hydroxyproline has similar or higher contribution than glycine in chiral responses, in which little to no signals from proline are detectable.

    v-SFG data for carboxylated and uncarboxylated osteocalcin respectively reveal that carboxylated osteocalcin has α-helices in the structure when Ca2+ ions are present in the solution, while the uncarboxylated version does not. Orientations for osteocalcin adsorbed onto hydrophobic, positively charged and negatively charged surfaces were determined by dividing peak areas of fragments from leucine, cysteine and carboxyglutamic acids from the positive Time-of-Flight Secondary Ion Mass Spectrometry (ToF-SIMS) spectra.

    Also, it was exercised to find the v-SFG signal with a femtosecond SFG system by utilizing the non-resonant background of a gold substrate and then delay the visible laser beam to only get signals from the vibrating molecules. Self-assembled monolayers (SAMs) prepared from dodecanethiols were used to demonstrate this principle, but the approach is valid also for other molecular systems.

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  • 27.
    Kandhasamy, Subramani
    et al.
    Central Leather Research Institute, India.
    Ramanathan, Giriprasath
    Central Leather Research Institute, India.
    Thangavelu, Muthukumar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Thyagarajan, SitaLakshmi
    Central Leather Research Institute, India.
    Umamaheshwari, Narayanan
    Central Leather Research Institute, India.
    Santhanakrishnan, V. P.
    TNAU, India.
    Tiruchirapalli Sivagnanam, Uma
    Central Leather Research Institute, India.
    Thirumalai Perumal, Paramasivan
    Central Leather Research Institute, India.
    Nanofibrous matrixes with biologically active hydroxybenzophenazine pyrazolone compound for cancer theranosticsx2017In: Materials science & engineering. C, biomimetic materials, sensors and systems, ISSN 0928-4931, E-ISSN 1873-0191, Vol. 74, p. 70-85Article, review/survey (Refereed)
    Abstract [en]

    The nanomaterial with the novel biologically active compounds has been actively investigated for application in cancer research. Substantial use of nanofibrous scaffold for cancer research with potentially bioactive compounds through electrospinning has not been fully explored. Here, we describe the series of fabrication of nanofibrous scaffold loaded with novel potential biologically active hydroxybenzo[a]phenazine pyrazol-5(4H)-one derivatives were designed, synthesized by a simple one-pot, two step four component condensation based on Michael type addition reaction of lawsone, benzene-1,2-diamine, aromatic aldehydes and 3-methyl-1-phenyl-1H-pyrazol-5 (4H)-one as the substrates. The heterogeneous solid state catalyst (Fe (III) Y-Zeolite) could effectively catalyze the reaction to obtain the product with high yield and short reaction time. The synthesized compounds (5a-5p) were analyzed by NMR, FTIR and HRMS analysis. Compound 5c was confirmed by single crystal XRD studies. All the compounds were biologically evaluated for their potential inhibitory effect on anticancer (MCF-7, Hep-2) and microbial (MRSA, MTCC 201 and FRCA) activities. Among the compounds 5i exhibited the highest levels of inhibitory activity against both MCF-7, Hep-2 cell lines. Furthermore, the compound 5i (BPP) was evaluated for DNA fragmentation, flow cytometry studies and cytotoxicity against MCF-7, Hep-2 and NIH 3T3 fibroblast cell lines. In addition, molecular docking (PDB ID: 1T46) studies were performed to predict the binding affinity of ligand with receptor. Moreover, the synthesized BPP compound was loaded in to the PHB-PCL nanofibrous scaffold to check the cytotoxicity against the MCF-7, Hep-2 and NIH 3T3 fibroblast cell lines. The in vitro apoptotic potential of the PHB-PCL-BPP nanofibrous scaffold was assessed against MCF-7, Hep-2 cancerous cells and fibroblast cells at 12, 24 and 48 h respectively. The nanofibrous scaffold with BPP can induce apoptosis and also suppress the proliferation of cancerous cells. We anticipate that our results can provide better potential research in nanomaterial based cancer research. (C) 2017 Elsevier B.V. All rights reserved.

  • 28.
    Khayyeri, Hanifeh
    et al.
    Lund University, Sweden.
    Blomgran, Parmis
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Hammerman, Malin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Turunen, Mikael J.
    University of Eastern Finland, Finland.
    Lowgren, Annika
    Lund University, Sweden.
    Guizar-Sicairos, Manuel
    Paul Scherrer Institute, Switzerland.
    Aspenberg, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Orthopaedics in Linköping.
    Isaksson, Hanna
    Lund University, Sweden.
    Achilles tendon compositional and structural properties are altered after unloading by botox2017In: Scientific Reports, E-ISSN 2045-2322, Vol. 7, article id 13067Article in journal (Refereed)
    Abstract [en]

    Tendon function and homeostasis rely on external loading. This study investigates the biological mechanisms behind tendon biomechanical function and how the mechanical performance is affected by reduced daily loading. The Achilles tendons of 16 weeks old female Sprague Dawley rats (n = 40) were unloaded for 5 weeks by inducing muscle paralysis with botulinum toxin injections in the right gastrocnemius and soleus muscles. The contralateral side was used as control. After harvest, the tendons underwent biomechanical testing to assess viscoelasticity (n = 30 rats) and small angle X-ray scattering to determine the structural properties of the collagen fibrils (n = 10 rats). Fourier transform infrared spectroscopy and histological staining (n = 10 rats) were performed to investigate the collagen and proteoglycan content. The results show that the stiffness increased in unloaded tendons, together with an increased collagen content. Creep and axial alignment of the collagen fibers were reduced. Stress-relaxation increased whereas hysteresis was reduced in response to unloading with botox treatment. Our findings indicate that altered matrix deposition relies on mechanical loading to reorganize the newly formed tissue, without which the viscoelastic behavior is impaired. The results demonstrate that reduced daily loading deprives tendons of their viscoelastic properties, which could increase the risk of injury.

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  • 29.
    Khayyeri, Hanifeh
    et al.
    Lund Univ, Sweden.
    Hammerman, Malin
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Lund Univ, Sweden.
    Turunen, Mikael J.
    Univ Eastern Finland, Finland.
    Blomgran, Parmis
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Notermans, Thomas
    Lund Univ, Sweden.
    Guizar-Sicairos, Manuel
    Paul Scherrer Inst, Switzerland.
    Eliasson, Pernilla T.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Aspenberg, Per
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Orthopaedics in Linköping.
    Isaksson, Hanna
    Lund Univ, Sweden.
    Diminishing effects of mechanical loading over time during rat Achilles tendon healing2020In: PLOS ONE, E-ISSN 1932-6203, Vol. 15, no 12, article id e0236681Article in journal (Refereed)
    Abstract [en]

    Mechanical loading affects tendon healing and recovery. However, our understanding about how physical loading affects recovery of viscoelastic functions, collagen production and tissue organisation is limited. The objective of this study was to investigate how different magnitudes of loading affects biomechanical and collagen properties of healing Achilles tendons over time. Achilles tendon from female Sprague Dawley rats were cut transversely and divided into two groups; normal loading (control) and reduced loading by Botox (unloading). The rats were sacrificed at 1, 2- and 4-weeks post-injury and mechanical testing (creep test and load to failure), small angle x-ray scattering (SAXS) and histological analysis were performed. The effect of unloading was primarily seen at the early time points, with inferior mechanical and collagen properties (SAXS), and reduced histological maturation of the tissue in unloaded compared to loaded tendons. However, by 4 weeks no differences remained. SAXS and histology revealed heterogeneous tissue maturation with more mature tissue at the peripheral region compared to the center of the callus. Thus, mechanical loading advances Achilles tendon biomechanical and collagen properties earlier compared to unloaded tendons, and the spatial variation in tissue maturation and collagen organization across the callus suggests important regional (mechano-) biological activities that require more investigation.

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  • 30.
    Kozak Ljunggren, Monika
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Elizondo, Rodolfo A.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Edin, Joel
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Olsen, David
    FibroGen Incorporated, San Francisco, CA, USA.
    Merrett, Kimberley
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences. Ottawa Hospital Research Institute–Vision Programme, Ottawa, Ontario, Canada.
    Lee, Chang-Jang
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Ottawa Hospital Research Institute–Vision Programme, Ottawa, Ontario, Canada.
    Salerud, Göran
    Linköping University, Department of Biomedical Engineering, Biomedical Instrumentation. Linköping University, The Institute of Technology.
    Polarek, James
    FibroGen Incorporated, San Francisco, CA, USA.
    Fagerholm, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Griffith, May
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Effect of Surgical Technique on Corneal Implant Performance2014In: Translational Vision Science & Technology, E-ISSN 2164-2591, Vol. 3, no 2, p. 1-13Article in journal (Refereed)
    Abstract [en]

    Purpose: Our aim was to determine the effect of a surgical technique on biomaterial implant performance, specifically graft retention.

     

    Methods: Twelve mini pigs were implanted with cell-free, 1-ethyl-3-(3-dimethyl aminopropyl) carbodiimide (EDC)/N-hydroxysuccinimide (NHS) cross-linked recombinant human collagen type III (RHCIII) hydrogels as substitutes for donor corneal allografts using overlying sutures with or without human amniotic membrane (HAM) versus interrupted sutures with HAM. The effects of the retention method were compared as well as the effects of collagen concentration (13.7% to 15% RHCIII).

    Results: All implanted corneas showed initial haze that cleared with time, resulting in corneas with optical clarity matching those of untreated controls. Biochemical analysis showed that by 12 months post operation, the initial RHCIII implants had been completely remodeled, as type I collagen, was the major collagenous protein detected, whereas no RHCIII could be detected. Histological analysis showed all implanted corneas exhibited regeneration of epithelial and stromal layers as well as nerves, along with touch sensitivity and tear production. Most neovascularization was seen in corneas stabilized by interrupted sutures.

    Conclusions: This showed that the surgical technique used does have a significant effect on the overall performance of corneal implants, overlying sutures caused less vascularization than interrupted sutures.

    Translational Relevance: Understanding the significance of the suturing technique can aid the selection of the most appropriate procedure when implanting artificial corneal substitutes. The same degree of regeneration, despite a higher collagen content indicates that future material development can progress toward stronger, more resistant implants.

  • 31.
    Lagali, Neil S
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Sensory Organs and Communication. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Rafat, Mehrdad
    Linköping University, Department of Biomedical Engineering, Division of Biomedical Engineering. Linköping University, Faculty of Science & Engineering. LinkoCare Life Sciences AB, Linköping, Sweden.
    Femtosecond Laser-Assisted Surgery for Implantation of Bioengineered Corneal Stroma to Promote Corneal Regeneration.2020In: Corneal Regeneration: Methods and Protocols / [ed] Mark Ahearne, New York: Humana Press, 2020, 1, Vol. 2145, p. 197-214Chapter in book (Refereed)
    Abstract [en]

    The femtosecond laser has achieved widespread use in ophthalmology owing to its ability to deliver focused high energy that is rapidly dissipated and thereby does not damage surrounding tissue outside the precise focal region. Extremely accurate and smooth cuts can be made by the laser, enabling a range of applications in anterior segment surgery. Minimally invasive corneal surgical procedures can be performed using the femtosecond laser, and here we describe the application of such procedures to improve implantation of bioengineered materials into the cornea. Bioengineered corneal tissue, including the collagenous corneal stroma, promises to provide a virtually unlimited supply of biocompatible tissue for treating multiple causes of corneal blindness globally, thereby circumventing problems of donor tissue shortages and access to tissue banking infrastructure. Optimal implantation of bioengineered materials, however, is required, in order to facilitate postoperative wound healing for the maintenance of corneal transparency and avoidance of postoperative complications such as scarring, inflammation, and neovascularization. Moreover, the avoidance of a detrimental physiological physiological wound healing response is critical for facilitating the corneal stromal regeneration enabled by the bioengineered stroma. Without proper implantation, the tissue response will favor inflammation and pathologic processes instead of quiescent keratocyte migration and new collagen production. Here we describe several procedures for optimized biomaterial implantation into the corneal stroma, that facilitate rapid wound healing and regenerative restoration of corneal transparency without the use of human donor tissue. A step-by-step methodology is provided for the use of the femtosecond laser and associated techniques, to enable seamless integration of bioengineered materials into the corneal stroma.

  • 32.
    Mak, Wing Cheung
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Sensor and Actuator Systems. Linköping University, Faculty of Science & Engineering. Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Magne, B.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Cheung, Kitt
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Atanasova, Diana
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Griffith, May
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. University of Montreal, Canada.
    Thermo-rheological responsive microcapsules for time-dependent controlled release of human mesenchymal stromal cells2017In: Biomaterials Science, ISSN 2047-4830, E-ISSN 2047-4849, Vol. 5, no 11, p. 2241-2250Article in journal (Refereed)
    Abstract [en]

    Human mesenchymal stromal cells (hMSCs) are adult-source cells that have been extensively evaluated for cell-based therapies. hMSCs delivered by intravascular injection have been reported to accumulate at the sites of injury to promote tissue repair and can also be employed as vectors for the delivery of therapeutic genes. However, the full potential of hMSCs remains limited as the cells are lost after injection due to anoikis and the adverse pathologic environment. Encapsulation of cells has been proposed as a means of increasing cell viability. However, controlling the release of therapeutic cells over time to target tissue still remains a challenge today. Here, we report the design and development of thermo-rheological responsive hydrogels that allow for precise, time dependent controlled-release of hMSCs. The encapsulated hMSCs retained good viability from 76% to 87% dependent upon the hydrogel compositions. We demonstrated the design of different blended hydrogel composites with modulated strength (S parameter) and looseness of hydrogel networks (N parameter) to control the release of hMSCs from thermoresponsive hydrogel capsules. We further showed the feasibility for controlled-release of encapsulated hMSCs within 3D matrix scaffolds. We reported for the first time by a systematic analysis that there is a direct correlation between the thermo-rheological properties associated with the degradation of the hydrogel composite and the cell release kinetics. This work therefore provides new insights into the further development of smart carrier systems for stem cell therapy.

  • 33.
    Mak, Wing Cheung
    et al.
    National University of Singapore.
    Yangzhong, Hong
    National University of Singapore.
    Trau, Dieter
    National University of Singapore.
    Real time observation of diffusion and bioaffinity binding processes in single polyelectrolyte-coated microcapsules: A fluorescence-based approach2007In: Colloids and Surfaces B: Biointerfaces, ISSN 0927-7765, E-ISSN 1873-4367, Vol. 60, no 1, p. 125-130Article in journal (Refereed)
    Abstract [en]

    We report on using fluorescence microscopy to study, visualize and determine the diffusion phenomena into and bioaffinity binding within single microcapsules in real time by using biotin–fluorescein as diffusive species and encapsulated avidin as binding partner. Microcapsules were constructed by entrapment of avidin within an agarose matrix and encapsulated with polyelectrolyte layers by Layer-by-Layer (LbL) polyelectrolyte self assembly. A “ring” of high fluorescence intensity advancing with time towards the capsule centre was observed during incubation of capsules with fluorescent-labeled biotin. Fluorescence intensity was build up in capsule areas where binding to avidin occurred and was visualized in real time. A model for the diffusion process in microcapsules was developed and experimental data was plotted and fitted well with trends predicted by the model. The value of the diffusion coefficient for biotin–fluorescein was determined to be 3.5 × 10−8 cm2/s, which is comparable to literature values of similar sized molecules.

  • 34.
    Mireles, Miguel
    et al.
    Barcelona Inst Sci and Technol, Spain.
    Morales-Dalmau, Jordi
    Barcelona Inst Sci and Technol, Spain.
    Johansson, Johannes
    Linköping University, Department of Biomedical Engineering, Division of Biomedical Engineering. Linköping University, Faculty of Science & Engineering. Barcelona Inst Sci and Technol, Spain.
    Vidal-Rosas, Ernesto E.
    Barcelona Inst Sci and Technol, Spain.
    Vilches, Clara
    Barcelona Inst Sci and Technol, Spain.
    Martinez-Lozano, Mar
    Catalan Inst Oncol IDIBELL, Spain.
    Sanz, Vanesa
    Barcelona Inst Sci and Technol, Spain.
    de Miguel, Ignacio
    Barcelona Inst Sci and Technol, Spain.
    Casanovas, Oriol
    Catalan Inst Oncol IDIBELL, Spain.
    Quidant, Romain
    Barcelona Inst Sci and Technol, Spain; ICREA, Spain.
    Durduran, Turgut
    Barcelona Inst Sci and Technol, Spain; ICREA, Spain.
    Non-invasive and quantitative in vivo monitoring of gold nanoparticle concentration and tissue hemodynamics by hybrid optical spectroscopies2019In: Nanoscale, ISSN 2040-3364, E-ISSN 2040-3372, Vol. 11, no 12, p. 5595-5606Article in journal (Refereed)
    Abstract [en]

    Owing to their unique combination of chemical and physical properties, inorganic nanoparticles show a great deal of potential as suitable agents for early diagnostics and less invasive therapies. Yet, their translation to the clinic has been hindered, in part, by the lack of non-invasive methods to quantify their concentration in vivo while also assessing their effect on the tissue physiology. In this work, we demonstrate that diffuse optical techniques, employing near-infrared light, have the potential to address this need in the case of gold nanoparticles which support localized surface plasmons. An orthoxenograft mouse model of clear cell renal cell carcinoma was non-invasively assessed by diffuse reflectance and correlation spectroscopies before and over several days following a single intravenous tail vein injection of polyethylene glycol-coated gold nanorods (AuNRs-PEG). Our platform enables to resolve the kinetics of the AuNR-PEG uptake by the tumor in quantitative agreement with ex vivo inductively coupled plasma mass spectroscopy. Furthermore, it allows for the simultaneous monitoring of local tissue hemodynamics, enabling us to conclude that AuNRs-PEG do not significantly alter the animal physiology. We note that the penetration depth of this current probe was a few millimeters but can readily be extended to centimeters, hence gaining clinical relevance. This study and the methodology presented here complement the nanomedicine toolbox by providing a flexible platform, extendable to other absorbing agents that can potentially be translated to human trials.

  • 35.
    Muthukumar, T.
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Biomedical Engineering. Linköping University, Faculty of Science & Engineering. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Sreekumar, G.
    Dept. of Biotechnology, St.Josephs College of Engineering, Sholinganallur, Tamilnadu, India.
    Sastry, T. P.
    Formerly Bio products laboratory, Central Leather Research Institute, Adyar, Tamilnadu, India.
    Chamundeeswari, M.
    Dept. of Biotechnology, St.Josephs College of Engineering, Sholinganallur, Tamilnadu, India.
    COLLAGEN AS A POTENTIAL BIOMATERIAL IN BIOMEDICAL APPLICATIONS2018In: Reviews on Advanced Materials Science, ISSN 1606-5131, E-ISSN 1605-8127, Vol. 53, no 1, p. 29-39Article in journal (Refereed)
    Abstract [en]

    Collagen, a biopolymer finds its application in the preparation of pharmaceutical products that are used in wound management, ophthalmic, orthopaedic and oral surgeries. This wide applicability is due its special properties such as biodegradability, biocompatibility, easy availability and high versatility. Collagen is isolated from various sources such as bovine skin, fish skin, chicken skin, skin waste of marine organisms, solid wastes of leather industry, short tendons of slaughtered cattle and bone. The isolated collagen from biological wastes is found to be cost effective due to the adaptation of simple methods for its isolation when compared with other commercially available biological macromolecules. The functional groups such as amino and carboxylic acid present in collagen helps in its modification that suits for various end uses which include wound healing, ophthalmic defects, drug delivery and tissue engineering applications. These beneficial properties impart uniqueness to collagen molecule among the available bio molecules.

  • 36.
    Nilsson, Goran
    et al.
    Kalmar Cty Publ Dent Serv, Sweden; Dept Prosthodont Dent Specialist Clin, Sweden.
    Ellner, Stefan
    Kalmar Cty Publ Dent Serv, Sweden.
    Arnebrant, Liselott
    Fac Odontol, Sweden.
    Brudin, Lars
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Department of Clinical Physiology, Kalmar County, Kalmar, Sweden.
    Larsson, Christel
    Malmo Univ, Sweden.
    Loss of pulp vitality correlated with the duration of the interim restoration and the experience of the dentist: A retrospective study2023In: The Journal of prosthetic dentistry (Print), ISSN 0022-3913, E-ISSN 1097-6841, Vol. 130, no 6, p. 833-839Article in journal (Refereed)
    Abstract [en]

    Statement of problem. The second most common biological complication in fixed prosthodontics is loss of pulp vitality, which may lead to restoration loss. While reasons for loss of pulp vitality are unclear, 2 potential contributing factors, duration of the interim restoration and operator experience, have not been fully investigated.Purpose. The purpose of this retrospective study was to investigate whether the duration of the interim restoration or the experience of the dentist was correlated with loss of pulp vitality.Material and methods. Fixed prosthetic restorations placed between 2005 and 2012 were retrospectively analyzed. Abutment teeth supporting single-unti or multiunit restorations were evaluated regarding loss of pulp vitality. The Mann-Whitney U test and simple logistic regression were used, with a=.05 for the subsequent multiple logistic regression. The experience of dental professionals was defined by the number of treatments performed and coupled with failure rate by using an analysis of variance.Results. One hundred seventy-four dentists made 15 879 restorations, of which 1136 failed during the observation period, a failure rate of 7.2%. Two hundred fifty restorations were randomly selected from the failed restorations, and a corresponding 250 restorations were randomly selected from nonfailed restorations for the control group. Increased duration with interim replacement was linked to a higher risk of loss of pulp vitality (P&lt;.001). Failure rate in the dentist group varied from 0% to 100%. No significant differences in failure rate were found among dentists who did few restorations and those who performed larger numbers of restorations.Conclusions. The results of the present study suggest that operator experience does not affect failure rate. However, extended time with an interim restoration was a contributing factor to the loss of pulp vitality. (J Prosthet Dent 2023;130:833-9)

  • 37.
    Olofsson, Johanna
    et al.
    Applied Materials Science, Uppsala University, Sweden.
    Grehk, Mikael
    Sandvik Materials Technology; Sandviken, Sweden.
    Berlind, Torun
    Linköping University, Department of Physics, Chemistry and Biology, Applied Optics . Linköping University, The Institute of Technology.
    Persson, Cecilia
    Applied Materials Science, Uppsala University, Sweden.
    Jacobson, Staffan
    Applied Materials Science, Uppsala University, Sweden.
    Engqvist, Håkan
    Applied Materials Science, Uppsala University, Sweden.
    Evaluation of silicon nitride as a wear resistant and resorbable alternative for total hip joint replacement2012In: Biomatter, ISSN 2159-2527, E-ISSN 2159-2535, Vol. 2, no 2, p. 94-102Article in journal (Refereed)
    Abstract [en]

    Many of the failures of total joint replacements are related to tribology, i.e., wear of the cup, head and liner. Accumulation of wear particles at the implants can be linked to osteolysis which leads to bone loss and in the end aseptic implant loosening. Therefore it is highly desirable to reduce the generation of wear particles from the implant surfaces.

    Silicon nitride (Si3N4) has shown to be biocompatible and have a low wear rate when sliding against itself and is therefore a good candidate as a hip joint material. Furthermore, wear particles of Si3N4 are predicted to slowly dissolve in polar liquids and they therefore have the potential to be resorbed in vivo, potentially reducing the risk for aseptic loosening.

    In this study, it was shown that α-Si3N4-powder dissolves in PBS. Adsorption of blood plasma indicated a good acceptance of Si3N4 in the body with relatively low immune response. Si3N4 sliding against Si3N4 showed low wear rates both in bovine serum and PBS compared with the other tested wear couples. Tribofilms were built up on the Si3N4 surfaces both in PBS and in bovine serum, controlling the friction and wear characteristics.

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  • 38.
    Patra, Hirak Kumar
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biosensors and Bioelectronics. Linköping University, The Institute of Technology.
    Khaliq, Nisar Ul
    Linköping University, Department of Physics, Chemistry and Biology, Biosensors and Bioelectronics. Linköping University, The Institute of Technology.
    Romu, Thobias
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Biomedical Engineering, Medical Informatics. Linköping University, The Institute of Technology.
    Wiechec, Emilia
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology.
    Borga, Magnus
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Biomedical Engineering, Medical Informatics. Linköping University, The Institute of Technology.
    Turner, Anthony P. F.
    Linköping University, Department of Physics, Chemistry and Biology, Biosensors and Bioelectronics. Linköping University, The Institute of Technology.
    Tiwari, Ashutosh
    Linköping University, Department of Physics, Chemistry and Biology, Biosensors and Bioelectronics. Linköping University, The Institute of Technology.
    MRI-Visual Order–Disorder Micellar Nanostructures for Smart Cancer Theranostics2014In: Advanced Healthcare Materials, ISSN 2192-2640, Vol. 3, no 4, p. 526-535Article in journal (Refereed)
    Abstract [en]

    The development of MRI-visual order–disorder structures for cancer nanomedicine explores a pH-triggered mechanism for theragnosis of tumor hallmark functions. Superparamagnetic iron oxide nanoparticles (SPIONs) stabilized with amphiphilic poly(styrene)-b-poly(acrylic acid)-doxorubicin with folic acid (FA) surfacing are employed as a multi-functional approach to specifically target, diagnose, and deliver drugs via a single nanoscopic platform for cancer therapy. The functional aspects of the micellar nanocomposite is investigated in vitro using human breast SkBr3 and colon cancer HCT116 cell lines for the delivery, release, localization, and anticancer activity of the drug. For the first time, concentration-dependent T2-weighted MRI contrast for a monolayer of clustered cancer cells is shown. The pH tunable order–disorder transition of the core–shell structure induces the relative changes in MRI contrast. The outcomes elucidate the potential of this material for smart cancer theranostics by delivering non-invasive real-time diagnosis, targeted therapy, and monitoring the course and response of the action before, during, and after the treatment regimen.

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  • 39.
    Phopase, Jaywant
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, Faculty of Science & Engineering.
    Comment on "Short peptide analogs as alternatives to collagen in pro-regenerative corneal implants" by Jangamreddy JR et al.2019In: Acta Biomaterialia, ISSN 1742-7061, E-ISSN 1878-7568, Vol. 97, p. 691-691Article in journal (Other academic)
    Abstract [en]

    n/a

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  • 40.
    Pupkaite, Justina
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Collagen Hydrogels for Regenerative Medicine2020Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The need for regenerative therapies to repair damaged or deteriorated organs and tissues, such as heart, skin, and cornea, is rising due to donor shortage and aging of the world’s population. Many proposed regenerative therapeutic approaches include a combination of cells, bioactive compounds, and hydrogels. Although collagen hydrogels have shown a lot of promise in regenerative medicine research, there are still challenges in their design and application strategies. Therefore, this thesis describes the development of novel collagen hydrogel designs for improved use in tissue bonding, cell delivery, and myocardial infarction therapy applications.

    Firstly, a visible-light crosslinked collagen hydrogel for tissue photobonding was developed. Methacrylated collagen hydrogel was crosslinked using the photoinitiator rose Bengal and visible light. The properties of the resulting hydrogel were tunable by changing the hydrogel composition. Biomimetic and ex vivo skin models were used to demonstrate the ability of the hydrogel to bond tissues whose edges are separated. Additionally, using the hydrogel led to less scarring compared to traditional sutures in a mouse skin incision model.

    Secondly, collagen was modified with thiol groups to design a hydrogel crosslinked using the thiol-Michael addition click reaction for cell encapsulation and delivery. The hydrogels demonstrated excellent shear-thinning and self-healing properties, allowing for injection after the crosslinking was complete. Additionally, the hydrogels showed minimal swelling and maintained their shape in an aqueous buffer for a prolonged period. Cell encapsulation and delivery using the hydrogels was demonstrated in vitro with mesenchymal stromal cells and endothelial cells.

    Thirdly, recombinant human collagen III hydrogels were prepared by crosslinking the collagen with EDC and NHS. The hydrogels contained either 1% or 2% collagen. Therapeutic strategies for these hydrogels were investigated, including the timing and dosage of the treatment, in a mouse MI model. Comparing 1% hydrogel injection at a single early time point (3 h) and three time points (3 h, 7 and 14 days) post-MI revealed improved cardiac function, reduced scar size and inflammation, and increased vascularization in the single injection group. Additionally, increasing the collagen III dose to 2% in the hydrogel at a single early time point (3 h) injection did not confer any additional functional improvement compared to 1% and resulted in scar size and vascular density comparable to control (PBS injection). In summary, this work contributes to the development of collagen hydrogel therapies for regenerative medicine by presenting a visible-light crosslinked collagen hydrogel for tissue bonding, a novel click-crosslinked collagen hydrogel with excellent shear-thinning properties for cell delivery, and the use of a recombinant human collagen III hydrogel in post-MI therapy, highlighting the importance of optimizing the timing and dosage of biomaterial therapies.

    List of papers
    1. Collagen-Based Photoactive Agent for Tissue Bonding
    Open this publication in new window or tab >>Collagen-Based Photoactive Agent for Tissue Bonding
    Show others...
    2017 (English)In: ACS Applied Materials and Interfaces, ISSN 1944-8244, E-ISSN 1944-8252, Vol. 9, no 11, p. 9265-9270Article in journal (Refereed) Published
    Abstract [en]

    Using a combination of methacrylated, collagen and the photosensitizer rose Bengal, a new light-activated biomimetic material for tissue sutureless bonding was developed. This formulation was cross-linked using green light. In vivo tests in mice demonstrate the suitability of the material for sutureless wound closure.

    Place, publisher, year, edition, pages
    AMER CHEMICAL SOC, 2017
    Keywords
    tissue photobonding; rose Bengal; collagen; wound healing; cross-linking
    National Category
    Polymer Chemistry
    Identifiers
    urn:nbn:se:liu:diva-136583 (URN)10.1021/acsami.7b01984 (DOI)000397478100010 ()28282110 (PubMedID)
    Note

    Funding Agencies|Natural Sciences and Engineering Research Council (NSERC) [RGPIN- 2015-0632, 342107]; AFA Forsakring, Sweden; UOHI start-up grant [1255]; Burroughs Wellcome Fund

    Available from: 2017-04-21 Created: 2017-04-21 Last updated: 2020-03-23
    2. Injectable Shape-Holding Collagen Hydrogel for Cell Encapsulation and Delivery Cross-linked Using Thiol-Michael Addition Click Reaction
    Open this publication in new window or tab >>Injectable Shape-Holding Collagen Hydrogel for Cell Encapsulation and Delivery Cross-linked Using Thiol-Michael Addition Click Reaction
    2019 (English)In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 20, no 9, p. 3475-3484Article in journal (Refereed) Published
    Abstract [en]

    Injectable hydrogels based on extracellular matrix-derived polymers show much promise in the field of tissue engineering and regenerative medicine. However, the hydrogels reported to date have at least one characteristic that limits their potential for clinical use, such as excessive swelling, complicated and potentially toxic cross-linking process, or lack of shear thinning and self-healing properties. We hypothesized that a collagen hydrogel cross-linked using thiol-Michael addition click reaction would be able to overcome these limitations. To this end, collagen was modified to introduce thiol groups, and hydrogels were prepared by cross-linking with 8-arm polyethylene glycol-maleimide. Rheological measurements on the hydrogels revealed excellent shear-thinning and self-healing properties. Additionally, only minimal swelling (6%) was observed over a period of 1 month in an aqueous buffer solution. Finally, tests using mesenchymal stromal cells and endothelial cells showed that the hydrogels are cell-compatible and suitable for cell encapsulation and delivery. Thus, the reported thiolated-collagen hydrogel cross-linked using thiol-Michael addition click reaction overcomes most of the challenges in the injectable hydrogel design and is an excellent candidate for cell delivery in regenerative medicine and tissue engineering applications. The hydrogel reported here is the first example of a self-healing hydrogel containing covalent cross-links.

    Place, publisher, year, edition, pages
    American Chemical Society, 2019
    National Category
    Biomaterials Science
    Identifiers
    urn:nbn:se:liu:diva-164539 (URN)10.1021/acs.biomac.9b00769 (DOI)000485211000027 ()
    Available from: 2020-03-23 Created: 2020-03-23 Last updated: 2020-11-12Bibliographically approved
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  • 41.
    Pupkaite, Justina
    et al.
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Polymer Chemistry, Department of Chemistry, Uppsala University, Uppsala, Sweden; Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Canada.
    Rosenquist, Jenny
    Polymer Chemistry, Department of Chemistry, Uppsala University, Uppsala, Sweden.
    Hilborn, Jöns
    Polymer Chemistry, Department of Chemistry, Uppsala University, Uppsala, Sweden.
    Samanta, Ayan
    Polymer Chemistry, Department of Chemistry, Uppsala University, Uppsala, Sweden.
    Injectable Shape-Holding Collagen Hydrogel for Cell Encapsulation and Delivery Cross-linked Using Thiol-Michael Addition Click Reaction2019In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 20, no 9, p. 3475-3484Article in journal (Refereed)
    Abstract [en]

    Injectable hydrogels based on extracellular matrix-derived polymers show much promise in the field of tissue engineering and regenerative medicine. However, the hydrogels reported to date have at least one characteristic that limits their potential for clinical use, such as excessive swelling, complicated and potentially toxic cross-linking process, or lack of shear thinning and self-healing properties. We hypothesized that a collagen hydrogel cross-linked using thiol-Michael addition click reaction would be able to overcome these limitations. To this end, collagen was modified to introduce thiol groups, and hydrogels were prepared by cross-linking with 8-arm polyethylene glycol-maleimide. Rheological measurements on the hydrogels revealed excellent shear-thinning and self-healing properties. Additionally, only minimal swelling (6%) was observed over a period of 1 month in an aqueous buffer solution. Finally, tests using mesenchymal stromal cells and endothelial cells showed that the hydrogels are cell-compatible and suitable for cell encapsulation and delivery. Thus, the reported thiolated-collagen hydrogel cross-linked using thiol-Michael addition click reaction overcomes most of the challenges in the injectable hydrogel design and is an excellent candidate for cell delivery in regenerative medicine and tissue engineering applications. The hydrogel reported here is the first example of a self-healing hydrogel containing covalent cross-links.

  • 42.
    Rajendran, Vijayalakshmi
    et al.
    University of Aberdeen, Scotland.
    Netukova, Magdalena
    Charles University of Prague, Czech Republic.
    Griffith, May
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. University of Montreal, Canada.
    Forrester, John V.
    University of Aberdeen, Scotland; University of Western Australia, Australia; Lions Eye Institute, Australia.
    Kuffova, Lucia
    University of Aberdeen, Scotland.
    Mesenchymal stem cell therapy for retro-corneal membrane - A clinical challenge in full-thickness transplantation of biosynthetic corneal equivalents2017In: Acta Biomaterialia, ISSN 1742-7061, E-ISSN 1878-7568, Vol. 64, p. 346-356Article in journal (Refereed)
    Abstract [en]

    Artificial corneas (keratoprostheses) and biosynthetic collagen-based corneal equivalents are surgical implants designed to ease the global burden of corneal blindness. However, keratoprostheses in many cases fail due to development of fibrous retro-corneal membranes (RCM). Fibrous membranes which develop in the anterior chamber after prosthesis implantation do so on a matrix of fibrin. This study investigated fibrin deposition and RCM formation after full-thickness collagen-based hydrogel implants and compared them with syngeneic and allogeneic corneal grafts in mice. Fibrin cleared from the anterior chamber within 14 days in both allo- and syn-grafts but, persisted in hydrogel implants and developed into dense retro-corneal membrane (RCM) which were heavily infiltrated by activated myofibroblasts. In contrast, the number of CD11 b(+) macrophages infiltrating the initial deposition of fibrin in the anterior chamber (AC) after hydrogel implantation was markedly reduced compared to syn- and allo-grafts. Inoculation of mesenchymal stem cells prior to collagen gel implant promoted clearance of gel associated fibrin from the anterior chamber. We propose that a failure of macrophage-mediated clearance of fibrin may be the cause of RCM formation after collagen-based hydrogel implants and that mesenchymal stem cell therapy promotes clearance of fibrin and prevents RCM formation. Statement of Significance The manuscript addresses the potential value of bone marrow-derived mesenchymal stem cell therapy for retro-corneal membrane (RCM) formation in full-thickness transplantation of biosynthetic corneal equivalents. This work reports the pathophysiological changes in the anterior chamber of the mouse eye following full-thickness recombinant human cross-linked collagen-based hydrogel implants in which persistent fibrin promotes the development of dense RCM. Furthermore, pre-treatment with mesenchymal stem cells reduces RCM formation and enhances corneal transparency. (C) 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

  • 43.
    Rasti Boroojeni, Fatemeh
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biophysics and bioengineering. Linköping University, Faculty of Science & Engineering. Sharif Univ Technol, Iran.
    Mashayekhan, Shohreh
    Sharif Univ Technol, Iran.
    Abbaszadeh, Hojjat-Allah
    Shahid Beheshti Univ Med Sci, Iran; Shahid Beheshti Univ Med Sci, Iran.
    Ansarizadeh, Mohamadhasan
    Sharif Univ Technol, Iran; Univ Oulu, Finland.
    Khoramgah, Maryam-Sadat
    Shahid Beheshti Univ Med Sci, Iran.
    Movaghar, Vafa Rahimi
    Univ Tehran Med Sci, Iran.
    Bioinspired Nanofiber Scaffold for Differentiating Bone Marrow-Derived Neural Stem Cells to Oligodendrocyte-Like Cells: Design, Fabrication, and Characterization2020In: International Journal of Nanomedicine, ISSN 1176-9114, E-ISSN 1178-2013, Vol. 15, p. 3903-3920Article in journal (Refereed)
    Abstract [en]

    Background: Researchers are trying to study the mechanism of neural stem cells (NSCs) differentiation to oligodendrocyte-like cells (OLCs) as well as to enhance the selective differentiation of NSCs to oligodendrocytes. However, the limitation in nerve tissue accessibility to isolate the NSCs as well as their differentiation toward oligodendrocytes is still challenging. Purpose: In the present study, a hybrid polycaprolactone (PCL)-gelatin nanofiber scaffold mimicking the native extracellular matrix and axon morphology to direct the differentiation of bone marrow-derived NSCs to OLCs was introduced. Materials and Methods: In order to achieve a sustained release of T3, this factor was encapsulated within chitosan nanoparticles and chitosan-loaded T3 was incorporated within PCL nanofibers. Polyaniline graphene (PAG) nanocomposite was incorporated within gelatin nanofibers to endow the scaffold with conductive properties, which resemble the conductive behavior of axons. Biodegradation, water contact angle measurements, and scanning electron microscopy (SEM) observations as well as conductivity tests were used to evaluate the properties of the prepared scaffold. The concentration of PAG and T3-loaded chitosan NPs in nanofibers were optimized by examining the proliferation of cultured bone marrow-derived mesenchymal stem cells (BMSCs) on the scaffolds. The differentiation of BMSCs-derived NSCs cultured on the fabricated scaffolds into OLCs was analyzed by evaluating the expression of oligodendrocyte markers using immunofluorescence (ICC), RT-PCR and flowcytometric assays. Results: Incorporating 2% PAG proved to have superior cell support and proliferation while guaranteeing electrical conductivity of 10.8 x 10(-5) S/cm. Moreover, the scaffold containing 2% of T3-loaded chitosan NPs was considered to be the most biocompatible samples. Result of ICC, RTPCR and flow cytometry showed high expression of O4, Olig2, platelet-derived growth factor receptor-alpha (PDGFR-alpha), O1, myelin/oligodendrocyte glycoprotein (MOG) and myelin basic protein (MBP) high expressed but low expression of glial fibrillary acidic protein (GFAP). Conclusion: Considering surface topography, biocompatibility, electrical conductivity and gene expression, the hybrid PCL/gelatin scaffold with the controlled release of T3 may be considered as a promising candidate to be used as an in vitro model to study patient-derived oligodendrocytes by isolating patients BMSCs in pathological conditions such as diseases or injuries. Moreover, the resulted oligodendrocytes can be used as a desirable source for transplanting in patients.

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  • 44.
    Richter, Maja
    Linköping University, Department of Physics, Chemistry and Biology, Applied Physics .
    Study of immune and haemostatic response induced by protein multilayers.2010Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    FibMat2.0 is a fibrinogen multilayer developed by AddBIO. Other proteins such as immunoglobulin G (IgG) and human serum albumin (HSA) can also be used to build multilayers with the same technique. The aim of this study of FibMat2.0 was to investigate if the manufacturing of the protein multilayer would induce an immune or haemostatic response in the body. The multilayers of IgG and HSA were also studied. Methods such as null ellipsometry, imaging of coagulation and the cone-and-plate setup were used to study immune reactions, activation of the coagulation cascade, and stability of the multilayers.

    Small amounts of plasma proteins were adsorbed to fibrinogen multilayers, but complement proteins adsorbed only to the IgG matrix and high molecular weight kininogen (HMWK) adsorbed only to the HSA monolayer. The imaging of coagulation method indicated that the titanium surface and the HSA monolayer activate surface induced coagulation rapidly, whereas fibrinogen and IgG multilayers demonstrated longer coagulation times. Platelets and a few white blood cells were bound to titanium surfaces and fibrinogen multilayers, but not to IgG multilayers or HSA monolayers.

    A conclusion in this study is that the surface of an implant can be coated with FibMat2.0 without any risks, but more studies are needed to better understand the interactions between the surfaces prepared in the present study and the immune and the haemostatic systems of the human body.

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  • 45.
    Sandberg, Olof
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Aspenberg, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Orthopaedics in Linköping.
    Glucocorticoids inhibit shaft fracture healing but not metaphyseal bone regeneration under stable mechanical conditions2015In: Bone & Joint Research, E-ISSN 2046-3758, Vol. 4, no 10, p. 170-175Article in journal (Refereed)
    Abstract [en]

    Objectives Healing in cancellous metaphyseal bone might be different from midshaft fracture healing due to different access to mesenchymal stem cells, and because metaphyseal bone often heals without a cartilaginous phase. Inflammation plays an important role in the healing of a shaft fracture, but if metaphyseal injury is different, it is important to clarify if the role of inflammation is also different. The biology of fracture healing is also influenced by the degree of mechanical stability. It is unclear if inflammation interacts with stability-related factors.

    Methods We investigated the role of inflammation in three different models: a metaphyseal screw pull-out, a shaft fracture with unstable nailing (IM-nail) and a stable external fixation (ExFix) model. For each, half of the animals received dexamethasone to reduce inflammation, and half received control injections. Mechanical and morphometric evaluation was used.

    Results As expected, dexamethasone had a strong inhibitory effect on the healing of unstable, but also stable, shaft fractures. In contrast, dexamethasone tended to increase the mechanical strength of metaphyseal bone regenerated under stable conditions.

    Conclusions It seems that dexamethasone has different effects on metaphyseal and diaphyseal bone healing. This could be explained by the different role of inflammation at different sites of injury.

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  • 46.
    Selegård, Robert
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
    Aronsson, Christopher
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
    Brommesson, Caroline
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Surface Physics and Nano Science. Linköping University, Faculty of Science & Engineering.
    Dånmark, Staffan
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
    Aili, Daniel
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
    Folding driven self-assembly of a stimuli-responsive peptide-hyaluronan hybrid hydrogel2017In: Scientific Reports, E-ISSN 2045-2322, Vol. 7, article id 7013Article in journal (Refereed)
    Abstract [en]

    Protein-metal ion interactions are ubiquitous in nature and can be utilized for controlling the self-assembly of complex supramolecular architectures and materials. Here, a tunable supramolecular hydrogel is described, obtained by self-assembly of a Zn2+-responsive peptide-hyaluronic acid hybrid synthesized using strain promoted click chemistry. Addition of Zn2+ triggers folding of the peptides into a helix-loop-helix motif and dimerization into four-helix bundles, resulting in hydrogelation. Removal of the Zn2+ by chelators results in rapid hydrogel disassembly. Degradation of the hydrogels can also be time-programed by encapsulation of a hydrolyzing enzyme within the gel, offering multiple possibilities for modulating materials properties and release of encapsulated species. The hydrogel further shows potential antioxidant properties when evaluated using an in vitro model for reactive oxygen species.

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  • 47.
    Shah, Furqan A.
    et al.
    Univ Gothenburg, Sweden; BIOMATCELL VINN Excellence Ctr Biomat and Cell Ther, Sweden.
    Stoica, Adrian
    Masaryk Univ, Czech Republic.
    Cardemil, Carina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Maxillofacial Unit. Univ Gothenburg, Sweden; BIOMATCELL VINN Excellence Ctr Biomat and Cell Ther, Sweden.
    Palmquist, Anders
    Univ Gothenburg, Sweden; BIOMATCELL VINN Excellence Ctr Biomat and Cell Ther, Sweden.
    Multiscale characterization of cortical bone composition, microstructure, and nanomechanical properties in experimentally induced osteoporosis2018In: Journal of Biomedical Materials Research. Part A, ISSN 1549-3296, E-ISSN 1552-4965, Vol. 106, no 4, p. 997-1007Article in journal (Refereed)
    Abstract [en]

    Cortical bone plays a vital role in determining overall bone strength. We investigate the structural, compositional, and nanomechanical properties of cortical bone following ovariectomy (OVX) of 12-week-old Sprague Dawley rats, since this animal model is frequently employed to evaluate the performance of implantable biomaterials in compromised bone healing conditions. Morphological parameters and material properties of bone in the geometrical center of the femoral cortex were investigated four and eight weeks post-OVX and in unoperated controls (Ctrl), using X-ray micro-computed tomography, backscattered electron scanning electron microscopy, Raman spectroscopy, and nanoindentation. The OVX animals showed increase in body weight, diminished bone mineral density, increased intracortical porosity, but increased bone mass through periosteal apposition (e.g., increases in periosteal perimeter, cortical cross-sectional thickness, and cross-sectional area). However, osteocyte densities, osteocyte lacunar dimensions, and the nanomechanical behavior on the single mineralized collagen fibril level remained unaffected. Our correlative multiscale investigation provides structural, chemical, and nanomechanical evidence substantiating earlier reports suggesting that rats ovariectomized at 12 weeks undergo simultaneous bone loss and growth, resulting in the effects of OVX being less obvious. Periosteal apposition contradicts the conventional view of bone loss in osteoporosis but appears advantageous for the greater functional demand imposed on the skeleton by increased body weight and fragility induced by increased intracortical porosity. Through a variety of morphological changes, it is likely that 12-week-old rats are able to adapt to OVX-related microstructural and compositional alterations. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 997-1007, 2018.

  • 48.
    Shrestha, Neha
    et al.
    Catholic University of Louvain, Belgium.
    Bouttefeux, Oriane
    Catholic University of Louvain, Belgium.
    Vanvarenberg, Kevin
    Catholic University of Louvain, Belgium.
    Lundquist, Patrik
    Uppsala University, Sweden.
    Cunarro, Juan
    University of Santiago de Compostela, Spain.
    Tovar, Sulay
    University of Santiago de Compostela, Spain.
    Khodus, Georgiy
    Uppsala University, Sweden.
    Andersson, Ellen
    Vrinnevi Hospital, Sweden.
    Keita, Åsa
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Gonzalez Dieguez, Carlos
    University of Santiago de Compostela, Spain.
    Artursson, Per
    Uppsala University, Sweden.
    Preat, Veronique
    Catholic University of Louvain, Belgium.
    Beloqui, Ana
    Catholic University of Louvain, Belgium.
    The stimulation of GLP-1 secretion and delivery of GLP-1 agonists &ITvia&IT nanostructured lipid carriers2018In: Nanoscale, ISSN 2040-3364, E-ISSN 2040-3372, Vol. 10, no 2, p. 603-613Article in journal (Refereed)
    Abstract [en]

    Nanoparticulate based drug delivery systems have been extensively studied to efficiently encapsulate and deliver peptides orally. However, most of the existing data mainly focus on the nanoparticles as a drug carrier, but the ability of nanoparticles having a biological effect has not been exploited. Herein, we hypothesize that nanostructured lipid carriers (NLCs) could activate the endogenous glucagon-like peptide-1 (GLP-1) secretion and also act as oral delivery systems for GLP-1 analogs (exenatide and liraglutide). NLCs effectively encapsulated the peptides, the majority of which were only released under the intestinal conditions. NLCs, with and without peptide encapsulation, showed effective induction of GLP-1 secretion in vitro from the enteroendocrinal L-cells (GLUTag). NLCs also showed a 2.9-fold increase in the permeability of exenatide across the intestinal cell monolayer. The intestinal administration of the exenatide and liraglutide loaded NLCs did not demonstrate any glucose lowering effect on normal mice. Further, ex vivo studies depicted that the NLCs mainly adhered to the mucus layer. In conclusion, this study demonstrates that NLCs need further optimization to overcome the mucosal barrier in the intestine; nonetheless, this study also presents a promising strategy to use a dual-action drug delivery nanosystem which synergizes its own biological effect and that of the encapsulated drug molecule.

  • 49.
    Simpson, Fiona
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Maisonneuve Rosemont Hosp Res Ctr, Canada; Univ Montreal, Canada; Ctr Hospitalier Univ Montreal, Canada.
    Mirazul Islam, Mohammad Mirazul
    Linköping University, Department of Biomedical and Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Massachusetts Eye & Ear & Schepens Eye Res Inst, MA USA.
    Buznyk, Oleksiy
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Sensory Organs and Communication. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping. Filatov Inst Eye Dis & Tissue Therapy NAMS Ukraine, Ukraine.
    Edin, Elle
    Linköping University, Department of Biomedical and Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Maisonneuve Rosemont Hosp Res Ctr, Canada; Univ Montreal, Canada; Ctr Hospitalier Univ Montreal, Canada; Uppsala Univ, Sweden.
    Groleau, Marc
    Maisonneuve Rosemont Hosp Res Ctr, Canada; Ctr Hospitalier Univ Montreal, Canada.
    Kozak Ljunggren, Monika
    Linköping University, Department of Biomedical and Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Magrelli, Federica M.
    Univ Modena & Reggio Emilia, Italy.
    AbuSamra, Dina B.
    Massachusetts Eye & Ear & Schepens Eye Res Inst, MA USA.
    Argueeso, Pablo
    Massachusetts Eye & Ear & Schepens Eye Res Inst, MA USA.
    Chodosh, James
    Massachusetts Eye & Ear & Schepens Eye Res Inst, MA USA.
    Liszka, Aneta
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology.
    Fagerholm, Per
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Sensory Organs and Communication. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Griffith, May
    Linköping University, Department of Biomedical and Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Maisonneuve Rosemont Hosp Res Ctr, Canada; Univ Montreal, Canada; Ctr Hospitalier Univ Montreal, Canada.
    Electron-Beam Irradiated Recombinant Human Collagen-Phosphorylcholine Corneal Implants Retain Pro-Regeneration Capacity2022In: Frontiers in Bioengineering and Biotechnology, E-ISSN 2296-4185, Vol. 10, article id 883977Article in journal (Refereed)
    Abstract [en]

    Sterilization of biodegradable, collagen-based implants is challenging as irradiation sterilization methods can alter their mechanical properties. Electron beam (EB) irradiation is a terminal sterilization method that has been used for biologically-derived implants. Here, recombinant human collagen type III-phosphorylcholine (RHCIII-MPC) hydrogels were irradiated with EB doses of 17, 19, or 21 kGy and their subsequent biocompatibility and ability to promote regeneration in rabbit corneas was evaluated. Unirradiated hydrogels stored in 1% chloroform in phosphate-buffered saline (C-PBS) were the controls. There were no significant differences between irradiated and non-irradiated samples in optical or physical properties (tensile strength, modulus, elasticity), or the ability to support cell growth. However, irradiated implants were more sensitive to high levels of collagenase than unirradiated controls and the C-PBS implants had increased cell growth compared to EB and controls at 72 h. Corneal implants e-beamed at 17 kGy or e-beamed and subsequently frozen (EB-F) to increase shelf-life showed no adverse biological effects of the irradiation. EB, EB-F, and C-PBS implanted corneas all rapidly re-epithelialized but showed mild neovascularization that resolved over 6 months. The regenerated neo-corneas were transparent at 6 months post-operation. In vivo confocal microscopy confirmed normal morphology for the epithelium, stroma, sub-basal nerves and unoperated endothelium. Histology showed that all the regenerated corneas were morphologically similar to the normal. Immunohistochemistry indicated the presence of a differentiated corneal epithelium and functional tear film. In conclusion, the e-beamed corneal implants performed as well as non-irradiated control implants, resulting in fully regenerated neo-corneas with new nerves and without blood vessels or inflammation that may impede vision or corneal function. Therefore, a complete validation study to establish EB irradiation as an effective means for corneal implant sterilization prior to clinical application is necessary as a next step.

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  • 50.
    Skyttner, Camilla
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
    Peptide-Liposome Model Systems for Triggered Release2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Liposomes are widely used in drug delivery to improve drug efficacy and to reduce side effects. For liposome-encapsulated drugs to become bioavailable and provide a therapeutic effect they must be released, which typically is a slow process that primarily relies on passive diffusion, liposome rupture or endocytotic uptake. Achieving drug concentrations within the therapeutic window can thus be challenging, resulting in poor efficacy and higher risks drug resistance. Finding means to modulate lipid membrane integrity and to trigger rapid and efficient release of liposomal cargo is thus critical to improve current and future liposomal drug delivery systems. The possibilities to tailor lipid composition and surface functionalization is vital for drug delivery applications but also make liposomes attractive model systems for studies of membrane active biomolecules.

    The overall aim of this thesis work has been to develop new strategies for triggering and controlling changes in lipid membrane integrity and to study the interactions of membrane active peptides with model lipid membranes using both de novo designed and biologically derived synthetic amphipathic cationic peptides. Two different sets of designed peptides have been explored that can fold and heterodimerize into a coiled coil and helix-loop-helix fourhelix bundle, respectively. Conjugation of the cationic lysine rich peptides to liposomes triggered a rapid and concentration dependent release. The additions of their corresponding glutamic acid-rich complementary peptides inhibited the release of liposomal cargo. Possibilities to reduce the inhibitory effect by both proteolytic digestion of the inhibitory peptide and by means of heterodimer exchange have been investigated. Moreover, the effects of peptide size and composition and ability to fold have been studied in order to elucidate the factors that influence the membrane permeabilizing effects of the peptides.

    In addition, the membrane activity of a the two-peptide bacteriocin PLNC8α and PLNC8β has been explored using liposomes as a model system. PLNC8αβ are expressed by Lactobacillus plantarum and were shown to display pronounced membrane-partition folding coupling, leading to rapid release of liposome encapsulated carboxyfluorescein. PLNC8αβ also kill and suppressed growth of the gram-negative bacteria Porphyromonas gingivalis by efficiently damaging the bacterial membrane.

    Although membrane active peptides are highly efficient in perturbing lipid membrane integrity, possibilities to trigger release using external stimuli are also of large interest for therapeutic applications. Light-induced heating of liposome encapsulated gold nanoparticles (AuNPs) has been shown by others as a potential strategy to trigger drug release. To facilitate fabrication of thermoplasmonic liposome systems we developed a simple method for synthesis of small AuNPs inside liposomes, using the liposomes as nanoscale reaction vessels.

    The work presented in this thesis provides new knowledge and techniques for future development of liposome-based drug delivery systems, peptide-based therapeutics and increase our understanding of peptide-lipid interactions.

    List of papers
    1. Tuning Liposome Membrane Permeability by Competitive Peptide Dimerization and Partitioning-Folding Interactions Regulated by Proteolytic Activity
    Open this publication in new window or tab >>Tuning Liposome Membrane Permeability by Competitive Peptide Dimerization and Partitioning-Folding Interactions Regulated by Proteolytic Activity
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    2016 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 6, no 21123, p. 1-9Article in journal (Refereed) Published
    Abstract [en]

    Membrane active peptides are of large interest for development of drug delivery vehicles and therapeutics for treatment of multiple drug resistant infections. Lack of specificity can be detrimental and finding routes to tune specificity and activity of membrane active peptides is vital for improving their therapeutic efficacy and minimize harmful side effects. We describe a de novo designed membrane active peptide that partition into lipid membranes only when specifically and covalently anchored to the membrane, resulting in pore-formation. Dimerization with a complementary peptide efficiently inhibits formation of pores. The effect can be regulated by proteolytic digestion of the inhibitory peptide by the matrix metalloproteinase MMP-7, an enzyme upregulated in many malignant tumors. This system thus provides a precise and specific route for tuning the permeability of lipid membranes and a novel strategy for development of recognition based membrane active peptides and indirect enzymatically controlled release of liposomal cargo.

    Place, publisher, year, edition, pages
    NATURE PUBLISHING GROUP, 2016
    National Category
    Physical Sciences Biochemistry and Molecular Biology
    Identifiers
    urn:nbn:se:liu:diva-126131 (URN)10.1038/srep21123 (DOI)000370532500002 ()26892926 (PubMedID)
    Note

    Funding Agencies|Linkoping University; Swedish Research Council (VR); Swedish Foundation for Strategic Research (SSF); Knut and Alice Wallenberg Foundation (KAW); Centre in Nanoscience and Technology (CeNano); Provost Office, NTU

    Available from: 2016-03-15 Created: 2016-03-15 Last updated: 2022-09-15
    2. Antibacterial effects of Lactobacillus and bacteriocin PLNC8 alpha beta on the periodontal pathogen Porphyromonas gingivalis
    Open this publication in new window or tab >>Antibacterial effects of Lactobacillus and bacteriocin PLNC8 alpha beta on the periodontal pathogen Porphyromonas gingivalis
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    2016 (English)In: BMC Microbiology, E-ISSN 1471-2180, Vol. 16, no 188Article in journal (Refereed) Published
    Abstract [en]

    Background: The complications in healthcare systems associated with antibiotic-resistant microorganisms have resulted in an intense search for new effective antimicrobials. Attractive substances from which novel antibiotics may be developed are the bacteriocins. These naturally occurring peptides are generally considered to be safe and efficient at eliminating pathogenic bacteria. Among specific keystone pathogens in periodontitis, Porphyromonas gingivalis is considered to be the most important pathogen in the development and progression of chronic inflammatory disease. The aim of the present study was to investigate the antimicrobial effects of different Lactobacillus species and the two-peptide bacteriocin PLNC8 alpha beta on P. gingivalis. Results: Growth inhibition of P. gingivalis was obtained by viable Lactobacillus and culture media from L. plantarum NC8 and 44048, but not L. brevis 30670. The two-peptide bacteriocin from L. plantarum NC8 (PLNC8 alpha beta) was found to be efficient against P. gingivalis through binding followed by permeabilization of the membranes, using Surface plasmon resonance analysis and DNA staining with Sytox Green. Liposomal systems were acquired to verify membrane permeabilization by PLNC8 alpha beta. The antimicrobial activity of PLNC8 alpha beta was found to be rapid (1 min) and visualized by TEM to cause cellular distortion through detachment of the outer membrane and bacterial lysis. Conclusion: Soluble or immobilized PLNC8 alpha beta bacteriocins may be used to prevent P. gingivalis colonization and subsequent pathogenicity, and thus supplement the host immune system against invading pathogens associated with periodontitis.

    Place, publisher, year, edition, pages
    BIOMED CENTRAL LTD, 2016
    Keywords
    Periodontitis; P. gingivalis; Lactobacillus; Bacteriocin; PLNC8
    National Category
    Microbiology
    Identifiers
    urn:nbn:se:liu:diva-131904 (URN)10.1186/s12866-016-0810-8 (DOI)000383422500001 ()27538539 (PubMedID)
    Note

    Funding Agencies|Swedish Heart-Lung Foundation; Foundation of Magnus Bergvall; Foundation of Olle Engkvist; Knowledge Foundation, Sweden

    Available from: 2016-10-13 Created: 2016-10-11 Last updated: 2024-01-17
    3. Liposomes as nanoreactors for the photochemical synthesis of gold nanoparticles
    Open this publication in new window or tab >>Liposomes as nanoreactors for the photochemical synthesis of gold nanoparticles
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    2015 (English)In: Journal of Colloid and Interface Science, ISSN 0021-9797, E-ISSN 1095-7103, Vol. 456, p. 206-209Article in journal (Refereed) Published
    Abstract [en]

    A simple and novel method for the photochemical synthesis of AuNPs in liposomes is described. Gold salt is co-encapsulated with the photoinitiator Irgacure-2959 in POPC liposomes prepared via traditional thin-film hydration technique. UVA irradiation for 15 min results in encapsulated AuNPs of 2.8 +/- 1.6 nm in diameter that are primarily dispersed in the aqueous interior of the liposomes. (C) 2015 Elsevier Inc. All rights reserved.

    Place, publisher, year, edition, pages
    Elsevier, 2015
    Keywords
    Liposomes; AuNPs; Nanoreactors
    National Category
    Clinical Medicine Physical Sciences
    Identifiers
    urn:nbn:se:liu:diva-120718 (URN)10.1016/j.jcis.2015.06.033 (DOI)000358458500027 ()26125517 (PubMedID)
    Note

    Funding Agencies|Swedish Foundation for Strategic Research (SSF); Center for Integrative Regenerative Medicine (IGEN) at Linkoping University

    Available from: 2015-08-24 Created: 2015-08-24 Last updated: 2018-08-22
    4. Tuning Liposome Membrane Permeability by Competitive Coiled Coil Heterodimerization and Heterodimer Exchange
    Open this publication in new window or tab >>Tuning Liposome Membrane Permeability by Competitive Coiled Coil Heterodimerization and Heterodimer Exchange
    2018 (English)In: Langmuir, ISSN 0743-7463, E-ISSN 1520-5827, Vol. 34, no 22, p. 6529-6537Article in journal (Refereed) Published
    Abstract [en]

    Membrane-active peptides that enable the triggered release of liposomal cargo are of great interest for the development of liposome-based drug delivery systems but require peptide-lipid membrane interactions that are highly defined and tunable. To this end, we have explored the possibility to use the competing interactions between membrane partitioning and heterodimenzation and the folding of a set of four different de novo designed coiled coil peptides Covalent conjugation of the cationic peptides triggered rapid destabilization of membrane mtegrity and the release of encapsulated species. The release was inhibited when introducing complementary peptides as a result of heterodimenzation and folding into coiled mils The degree of inhibition was shown to be dictated by the coiled coil peptide heterodimer dissociation constants, and liposomal release could be reactivated by a heterodimer exchange to render the membrane bound peptide free and thus membrane-active. The possibility to tune the permeability of lipid membranes using highly specific peptide-folding-dependent interactions delineates a new possible approach for the further development of responsive liposome-based drug delivery systems.

    Place, publisher, year, edition, pages
    AMER CHEMICAL SOC, 2018
    National Category
    Biophysics
    Identifiers
    urn:nbn:se:liu:diva-149349 (URN)10.1021/acs.langmuir.8b00592 (DOI)000434893600023 ()29758162 (PubMedID)
    Note

    Funding Agencies|Swedish Research Council (VR) [2017-04475]; Swedish Cancer Foundation [CAN 2017/430]; Swedish Government Strategic Research Area in Materials Science on Functional Materials at Linkoping University [2009-00971]

    Available from: 2018-07-02 Created: 2018-07-02 Last updated: 2019-01-22
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    Peptide-Liposome Model Systems for Triggered Release
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