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  • 1.
    Ajalloueian, Fatemeh
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Zeiai, Said
    Fossum, Magdalena
    Hilborn, Jöns G.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Constructs of electrospun PLGA, compressed collagen and minced urothelium for minimally manipulated autologous bladder tissue expansion2014In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 35, no 22, p. 5741-5748Article in journal (Refereed)
    Abstract [en]

    Bladder regeneration based on minced bladder mucosa in vivo expansion is an alternative to in vitro culturing of urothelial cells. Here, we present the design of a hybrid, electrospun poly(lactic-co-glycolide) (PLGA) - plastically compressed (PC) collagen scaffold that could allow in vivo bladder mucosa expansion. Optimisation of electrospinning was performed in order to obtain increased pore sizes and porosity to consolidate the construct and to support neovascularisation and tissue ingrowth. Tensile tests showed an increase in average tensile strength from 0.6 MPa for PC collagen to 3.57 MPa for the hybrid construct. The optimised PLGA support scaffold was placed between two collagen gels, and the minced tissue was distributed either on top or both on top and inside the construct prior to PC; this was then cultured for up to four weeks. Morphology, histology and SEM demonstrated that the construct maintained its integrity throughout cell culture. Cells from minced tissue migrated, expanded and re-organised to a confluent cell layer on the top of the construct after two weeks and formed a multilayered urothelium after four weeks. Cell morphology and phenotype was typical for urothelial mucosa during tissue culture. (C) 2014 Elsevier Ltd. All rights reserved.

  • 2.
    Almlöf, Martin
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Kristensen, Emma M. E.
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics.
    Siegbahn, Hans
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics.
    Åqvist, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Molecular dynamics study of heparin based coatings2008In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 29, no 33, p. 4463-4469Article in journal (Refereed)
    Abstract [en]

    Heparin based surface coatings can be used to improve the biocompatibility of metallic surfaces such as vascular stents. Here, we report molecular dynamics simulations of a macromolecular conjugate of heparin used to prepare such surfaces. The structural properties of the heparin conjugate are investigated for different degrees of hydration, to allow comparison with spectroscopic results. The simulations show that the polymer becomes more compact with an increasing degree of inter-chain interactions as the hydration increases. This is also accompanied by changes in the interaction patterns among the heparin chains, where counter ions become looser associated with the disaccharide units and their strong interactions can be partly replaced by water molecules and heparin hydroxyl groups. The structural information that can be obtained from computer simulations of this type of coatings can be very valuable for understanding and further development of functional interfaces, since very little is known experimentally regarding their detailed structural properties. (C) 2008 Elsevier Ltd. All rights reserved.

  • 3. Bayat, N
    et al.
    Lopes, Viviana
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Jensen, LD
    Cristobal, S
    Vascular toxicity of ultra-small TiO2 nanoparticles and single walled carbon nanotubes in vitro and in vivo2015In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 63, p. 1-13Article in journal (Refereed)
    Abstract [en]

    Ultra-small nanoparticles (USNPs) at 1-3 nm are a subset of nanoparticles (NPs) that exhibit intermediate physicochemical properties between molecular dispersions and larger NPs. Despite interest in their utilization in applications such as theranostics, limited data about their toxicity exist. Here the effect of TiO2-USNPs on endothelial cells in vitro, and zebrafish embryos in vivo, was studied and compared to larger TiO2-NPs (30 nm) and to single walled carbon nanotubes (SWCNTs). In vitro exposure showed that TiO2-USNPs were neither cytotoxic, nor had oxidative ability, nevertheless were genotoxic. In vivo experiment in early developing zebrafish embryos in water at high concentrations of TiO2-USNPs caused mortality possibly by acidifying the water and caused malformations in the form of pericardial edema when injected. Myo1C involved in glomerular development of zebrafish embryos was upregulated in embryos exposed to TiO2-USNPs. They also exhibited anti-angiogenic effects both in vitro and in vivo plus decreased nitric oxide concentration. The larger TiO2-NPs were genotoxic but not cytotoxic. SWCNTs were cytotoxic in vitro and had the highest oxidative ability. Neither of these NPs had significant effects in vivo. To our knowledge this is the first study evaluating the effects of TiO2-USNPs on vascular toxicity in vitro and in vivo and this strategy could unravel USNPs potential applications.

  • 4. Broos, Sissela
    et al.
    Sandin, Linda C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Apel, Jenny
    Tötterman, Thomas H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Akagi, Takami
    Akashi, Mitsuru
    Borrebaeck, Carl A. K.
    Ellmark, Peter
    Lindstedt, Malin
    Synergistic augmentation of CD40-mediated activation of antigen-presenting cells by amphiphilic poly(gamma-glutamic acid) nanoparticles2012In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 33, no 26, p. 6230-6239Article in journal (Refereed)
    Abstract [en]

    Agonistic anti-CD40 monoclonal antibodies (mAbs) hold great potential for cancer immunotherapy. However, systemic administration of anti-CD40 mAbs can be associated with severe side effects, such as cytokine release syndrome and liver damage. With the aim to increase the immunostimulatory potency as well as to achieve a local drug retention of anti-CD40 mAbs, we linked an agonistic mAb to immune activating amphiphilic poly(gamma-glutamic acid) nanoparticles (gamma-PGA NPs). We demonstrate that adsorption of anti-CD40 mAb to gamma-PGA NPs (anti-CD40-NPs) improved the stimulatory capacity of the CD40 agonist, resulting in upregulation of costimulatory CD80 and CD86 on antigen-presenting cells, as well as IL-12 secretion. Interestingly, anti-CD40-NP5 induced strong synergistic proliferative effects in B cells, possibly resulting from a higher degree of CD40 multimerization, enabled by display of multiple anti-CD40 mAbs on the NPs. In addition, local treatment with anti-CD40-NPs, compared to only soluble CD40 agonist, resulted in a significant reduction in serum levels of IL-6, IL-10, IL-12 and TNF-alpha in a bladder cancer model. Taken together, our results suggest that anti-CD40-NPs are capable of synergistically enhancing the immunostimulatory effect induced by the CD40 agonist, as well as minimizing adverse side effects associated with systemic cytokine release. This concept of nanomedicine could play an important role in localized immunotherapy of cancer.

  • 5.
    Bäck, Jennie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Lang, Markus Huber
    Elgue, Graciela
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Kalbitz, Miriam
    Sanchez, Javier
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Ekdahl, Kristina Nilsson
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Distinctive regulation of contact activation by antithrombin and C1-inhibitor on activated platelets and material surfaces2009In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 30, no 34, p. 6573-6580Article in journal (Refereed)
    Abstract [en]

    Activated human plate lets trigger FXII-mediated contact activation, which leads to the generation of FXIIa-antithrombin (AT) and FXIa-AT complexes. This suggests that contact activation takes place at different sites, on activated platelets and material surfaces, during therapeutic procedures involving biomaterials in contact with blood and is differentially regulated. Here we show that activation in platelet-poor plasma, platelet-rich plasma (PRP), and whole blood induced by glass, kaolin, and polyphosphate elicited high levels of FXIIa-C1-inhibitor (C1INH), low levels of FXIa-C1INH and KK-C1INH, and almost no AT complexes. Platelet activation, in both PRP and blood, led to the formation of FXIIa-AT, FXIa-AT, and kallikrein (KK)-AT but almost no C1INH complexes. In severe trauma patients, FXIIa-AT and FXIa-AT were correlated with the release of thrombospondin-1 (TSP-1) from activated platelets. In contrast, FXIIa-C1INH complexes were detected when the FXIIa-AT levels were low. No correlations were found between FXIIa-C1INH and FXIIa-AT or TSP-1. Inhibition of FXIIa on material surfaces was also shown to affect the function of aggregating platelets. In conclusion, formation of FXIIa-AT and FXIIa-C1INH complexes can help to distinguish between contact activation triggered by biomaterial surfaces and by activated platelets. Platelet aggregation studies also demonstrated that platelet function is influenced by material surface-mediated contact activation and that generation of FXIIa-AT complexes may serve as a new biomarker for thrombotic reactions during therapeutic procedures employing biomaterial devices.

  • 6.
    Dong, Yihui
    et al.
    Nanjing Tech Univ, State Key Lab Mat Oriented & Chem Engn, Nanjing 210009, Jiangsu, Peoples R China;Nanjing Tech Univ, Jiangsu Natl Synerget Innovat Ctr Adv Mat SICAM, Nanjing 210009, Jiangsu, Peoples R China;Luled Univ Technol, Div Energy Sci, S-97187 Lulea, Sweden.
    Ji, Xiaoyan
    Luled Univ Technol, Div Energy Sci, S-97187 Lulea, Sweden.
    Laaksonen, Aatto
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Structural Chemistry. Nanjing Tech Univ, State Key Lab Mat Oriented & Chem Engn, Nanjing 210009, Jiangsu, Peoples R China;Nanjing Tech Univ, Jiangsu Natl Synerget Innovat Ctr Adv Mat SICAM, Nanjing 210009, Jiangsu, Peoples R China;Stockholm Univ, Dept Mat & Environm Chem, Arrhenius Lab, SE-10691 Stockholm, Sweden;Petru Poni Inst Macromol Chem, Ctr Adv Res Bionanoconjugates & Biopolymers, Aleea Grigore Ghica Voda 41A, Iasi 700487, Romania.
    Cao, Wei
    Tsinghua Univ, State Key Lab Tribol, Beijing 100084, Peoples R China.
    An, Rong
    Nanjing Univ Sci & Technol, Herbert Gleiter Inst Nanosci, Nanjing 210094, Jiangsu, Peoples R China.
    Lu, Linghong
    Nanjing Tech Univ, State Key Lab Mat Oriented & Chem Engn, Nanjing 210009, Jiangsu, Peoples R China;Nanjing Tech Univ, Jiangsu Natl Synerget Innovat Ctr Adv Mat SICAM, Nanjing 210009, Jiangsu, Peoples R China.
    Lu, Xiaohua
    Nanjing Tech Univ, State Key Lab Mat Oriented & Chem Engn, Nanjing 210009, Jiangsu, Peoples R China;Nanjing Tech Univ, Jiangsu Natl Synerget Innovat Ctr Adv Mat SICAM, Nanjing 210009, Jiangsu, Peoples R China.
    Determination of the small amount of proteins interacting with TiO2 nanotubes by AFM-measurement2019In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 192, p. 368-376Article in journal (Refereed)
    Abstract [en]

    Detecting the small amounts of proteins interacting effectively with the solid film electrodes surface still remains a challenge. To address this, in this work, a new approach was proposed by the combination of the adhesion forces and the molecular interaction measured with AFM. Cytochrome c (Cyt C) interacting effectively with TiO2 nanotube arrays (TNAs) was chosen as a probe. The amounts of Cyt C molecules interacting effectively on TNAs surface (C-TNA) range from 5.5x10(-12) to 7.0x10(-12) mol/cm(2) (68.2-86.8 ng/cm(2)) and they are comparable with the values obtained by the electrochemistry method in the literature, in evidence of the accuracy of this AFM-based approach. The reliability of the proposed approach was further verified by conducting Surface Enhanced Raman Scattering (SERS) measurements and estimating the enhancement factor (EF). This interaction-based AFM approach can be used to accurately obtain the small amounts of adsorbed substances on the solid film electrodes surface in the applications such as biosensors, biocatalysis, and drug delivery, etc.

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

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

  • 8. Elgali, Ibrahim
    et al.
    Igawa, Kazuyo
    Palmquist, Anders
    Lenneras, Maria
    Xia, Wei
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Choi, Sungjin
    Chung, Ung-Il
    Omar, Omar
    Thomsen, Peter
    Molecular and structural patterns of bone regeneration in surgically created defects containing bone substitutes2014In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 35, no 10, p. 3229-3242Article in journal (Refereed)
    Abstract [en]

    Several biomaterials have been introduced for bone augmentation. However, information is lacking about the mechanisms of bone regeneration and/or integration of these materials in the recipient bone. This study aimed to determine the molecular and structural events in bone defects after augmentation with synthetic tetrapod-shaped calcium phosphate (Tetrabone; TetraB) compared with natural deproteinized bovine bone (DBB). Defects were created in the epiphyses of rat femurs and filled with TetraB or DBB or left empty (Sham). After 3, 6, 14 and 28 d, samples were harvested for histology, histomorphometry, ultrastructure and gene expression analyses. At 3 d, higher expressions of bone formation (ALP and DC) and remodeling (CatK) genes were detected in TetraB compared with DBB and Sham. Downregulation of bone remodeling genes (TRAP and CatK) was detected in DBB as compared to Sham after 14 d. Histomorphometry at 6 and 14 d demonstrated greater bone contact with the granules in TetraB. At 28 d, a larger bone area per defect was found in TetraB. The present experiments show that a synthetic substitute, consisting of alpha-tricalcium and octacalcium phosphates, induces early osteogenic and osteoclastic activities and promotes bone formation in trabecular bone defects.

  • 9. Engberg, Anna E.
    et al.
    Nilsson, Per H.
    Huang, Shan
    Fromell, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Hamad, Osama A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Mollnes, Tom Eirik
    Rosengren-Holmberg, Jenny P.
    Sandholm, Kerstin
    Teramura, Yuji
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Nicholls, Ian A.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Ekdahl, Kristina N.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Prediction of inflammatory responses induced by biomaterials in contact with human blood using protein fingerprint from plasma2015In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 36, p. 55-65Article in journal (Refereed)
    Abstract [en]

    Inappropriate complement activation is often responsible for incompatibility reactions that occur when biomaterials are used. Complement activation is therefore a criterion included in legislation regarding biomaterials testing. However, no consensus is yet available regarding appropriate complement-activation-related test parameters. We examined protein adsorption in plasma and complement activation/cytokine release in whole blood incubated with well-characterized polymers. Strong correlations were found between the ratio of C4 to its inhibitor C4BP and generation of 10 (mainly pro-inflammatory) cytokines, including IL-17, IFN-gamma, and IL-6. The levels of complement activation products correlated weakly (C3a) or not at all (C5a, sC5b-9), confirming their poor predictive values. We have demonstrated a direct correlation between downstream biological effects and the proteins initially adhering to an artificial surface after contact with blood. Consequently, we propose the C4/C4BP ratio as a robust, predictor of biocompatibility with superior specificity and sensitivity over the current gold standard.

  • 10. Engberg, Anna E.
    et al.
    Sandholm, Kerstin
    Bexborn, Fredrik
    Persson, Jenny
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Lindahl, Gunnar
    Ekdahl, Kristina Nilsson
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Inhibition of complement activation on a model biomaterial surface by streptococcal M protein-derived peptides2009In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 30, no 13, p. 2653-2659Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to evaluate a new approach to inhibit complement activation triggered by biomaterial surfaces in contact with blood. In order to inhibit complement activation initiated by the classical pathway (CP), we used streptococcal M protein-derived peptides that specifically bind human C4BP, an inhibitor of the CP. The peptides were used to coat polystyrene microtiter wells which served as a model biomaterial. The ability of coated peptides to bind C4BP and to attenuate complement activation via the CP (monitored as generation of fluid-phase C3a and binding of fragments of C3 and C4 to the surface) was investigated using diluted normal human serum, where complement activation by the AP is minimal, as well as serum from a patient lacking alternative pathway activation. Complement activation (all parameters) was significantly decreased in serum incubated in well surfaces coated with peptides. Total inhibition of complement activation was obtained at peptide coating concentrations as low as 1-5 microg/mL. Successful use of Streptococcus-derived peptides shows that it is feasible to control complement activation at a model biomaterial surface by capturing autologous complement regulatory molecules from plasma.

  • 11. Engelhardt, Eva-Maria
    et al.
    Micol, Lionel A.
    Houis, Stephanie
    Wurm, Florian M.
    Hilborn, Jöns
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Materials Chemistry, Polymer Chemistry.
    Hubbell, Jeffrey A.
    Frey, Peter
    A collagen-poly(lactic acid-co-epsilon-caprolactone) hybrid scaffold for bladder tissue regeneration2011In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 32, no 16, p. 3969-3976Article in journal (Refereed)
    Abstract [en]

    Scaffold materials should favor cell attachment and proliferation, and provide designable 3D structures with appropriate mechanical strength. Collagen matrices have proven to be beneficial scaffolds for tissue regeneration. However, apart from small intestinal submucosa, they offer a limited mechanical strength even if crosslinking can enhance their mechanical properties. A more cell-friendly way to increase material strength is to combine synthetic polymer meshes with plastic compressed collagen gels. This work describes the potential of plastic compressed collagen poly(lactic acid-co-epsilon-caprolactone) (PLAC) hybrids as scaffolds for bladder tissue regeneration. Human bladder smooth muscle and urothelial cells were cultured on and inside collagen PLAC hybrids in vitro. Scaffolds were analyzed by electron microscopy, histology, immunohistochemistry, and AlamarBlue assay. Both cell types proliferated in and on the hybrid, forming dense cell layers on top after two weeks. Furthermore, hybrids were implanted subcutaneously in the backs of nude mice. Host cell infiltration, scaffold degradation, and the presence of the seeded bladder cells were analyzed. Hybrids showed a lower inflammatory reaction in vivo than PLAC meshes alone, and first signs of polymer degradation were visible at six months. Collagen PLAC hybrids have potential for bladder tissue regeneration, as they show efficient cell seeding, proliferation, and good mechanical properties.

  • 12.
    Hong, Jaan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology and Transfusion Medicine. Klinisk immunologi.
    Nilsson Ekdahl, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology and Transfusion Medicine.
    Reynolds, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology and Transfusion Medicine.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology and Transfusion Medicine.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology and Transfusion Medicine.
    A new in vitro model to study interaction between whole blood and biomaterials. Studies of platelet and coagulation activation and the effect of aspirin1999In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 20, no 7, p. 603-611Article in journal (Refereed)
    Abstract [en]

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

  • 13. Huang, Shan
    et al.
    Engberg, Anna E.
    Linnaeus Univ, Ctr Biomat Chem, Kalmar, Sweden.;Univ & Reg Labs Reg, Dept Clin Chem, Skane, Sweden..
    Jonsson, Nina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Sandholm, Kerstin
    Nicholls, Ian A.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Mollnes, Tom Eirik
    Natl Hosp Norway, Oslo Univ Hosp, Dept Immunol, Oslo, Norway.;Univ Oslo, KG Jebsen ICR, N-0316 Oslo, Norway.;Nordland Hosp, Res Lab, Bodo, Norway.;Univ Tromso, Fac Hlth Sci, N-9001 Tromso, Norway.;Norwegian Univ Sci & Technol, Ctr Mol Inflammat Res, N-7034 Trondheim, Norway..
    Fromell, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Ekdahl, Kristina N.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Reciprocal relationship between contact and complement system activation on artificial polymers exposed to whole human blood2016In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 77, p. 111-119Article in journal (Refereed)
    Abstract [en]

    Background: Inappropriate and uncontrolled activation of the cascade systems in the blood is a driving force in adverse inflammatory and thrombotic reactions elicited by biomaterials, but limited data are available on the activation of the contact system by polymers and the present study was undertaken to investigate these mechanisms in established models. Methods: Polymer particles were incubated in (1) EDTA-plasma (10 mM) to monitor the adsorption of 20 selected proteins; (2) lepirudin-anticoagulated plasma to evaluate contact system activation, monitored by the formation of complexes between the generated proteases factor[F]XIIa, FXIa and kallikrein and the serpins C1-inhibitor [C1INH] and antithrombin [AT]; (3) lepirudin-anticoagulated whole blood to determine cytokine release. Results: Strong negative correlations were found between 10 cytokines and the ratio of deposited FXII/C1INH, generated FXIIa-C1INH complexes, and kallikrein-C1INH complexes. Formation of FXIIa-C1INH complexes correlated negatively with the amount of C3a and positively with deposited IgG. Conclusions: A reciprocal relationship was found between activation of the contact system and the complement system induced by the polymers studied here. The ratios of FXII/C1INH or C4/C4BP, adsorbed from EDTA-plasma are useful surrogate markers for cytokine release and inflammatory response to materials intended for blood contact.

  • 14. Izquierdo-Barba, Isabel
    et al.
    Vallet-Regí, María
    Kupferschmidt, Natalia
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Terasaki, Osamu
    Schmidtchen, Artur
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Incorporation of antimicrobial compounds in mesoporous silica film monolith2009In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 30, no 29, p. 5729-5736Article in journal (Refereed)
    Abstract [en]

    Incorporation of the antimicrobial peptide LL-37 (LLGDFFRKSKEKIGKEFKRIVQRIKDFLRNLVPRTES), as well as low molecular weight antimicrobial chlorhexidine, into mesoporous silica was obtained using an EISA one-pot synthesis method. FTIR confirmed efficient encapsulation of both LL-37 and chlorhexidine into mesoporous silica, while XRD and TEM showed that antimicrobial agent incorporation can be achieved without greatly affecting the structure of the mesoporous silica. The modified mesoporous silica released LL-37 and chlorhexidine slowly, reaching maximum release after about 200 h. The release rate could also be controlled through incorporation of SH groups in the pore walls, adding to pore hydrophobicity and reducing the release rate by about 50% compared to the unmodified mesoporous silica. Mesoporous silica containing either LL-37 or chlorhexidine displayed potent bactericidal properties against both Gram-positive Staphylococcus aureus and Gram-negative Escherichia coli. While chlorhexidine-loaded mesoporous silica displayed an accompanying high toxicity, as judged from hemolysis, LDH release, and MTT assay, the corresponding material containing LL-37 showed very low toxicity by all these assays, comparable to that observed for mesoporous silica in the absence of antibacterial drug, as well as to the negative controls in the respective assays. Mesoporous silica containing LL-37 therefore holds potential as an implantable material or a surface coating for such materials, as it combines potent bactericidal action with low toxicity, important features for controlling implant-related infections, e.g., for multi-resistant pathogens or for cases where access to the infection site of systemically administered antibiotics is limited due to collagen capsule formation or other factors.

  • 15.
    Johnell, Matilda
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Larsson, R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    The influence of different heparin surface concentrations and antithrombin-binding capacity on inflammation and coagulation2005In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 26, no 14, p. 1731-1739Article in journal (Other academic)
    Abstract [en]

    The corline heparin surface (CHS) used in the extracorporeal circuit during coronary artery bypass grafting is shown to decrease the activation of inflammation and coagulation. Synchrotron radiation studies have shown that a single layer of the CHS may not completely cover the substrate surface. However, a double layer of CHS results in a uniform surface. We investigated the effect of surfaces with different surface concentrations of heparin on cell activation and coagulation compared to an uncoated surface. The CHS is prepared by a conditioning layer of polymeric amine onto which a macromolecular heparin conjugate is attached. We used PVC tubing, uncoated or modified with a single or double layer of the CHS, and circulated fresh whole blood from healthy volunteers in a loop model system at 37 degrees C up to 4 h. Blood was drawn from the loops at different times and activation of inflammation and coagulation was studied by real-time PCR, flow cytometry and ELISA. The activation of leukocytes and platelets and formation of leukocyte-platelet aggregates were reduced by use of the single-layered CHS compared to the uncoated surface. Use of double-layered CHS resulted in significantly reduced cell activation and thrombin generation. Development of the CHS obtained by the double layer of the coating has improved the biocompatibility of the surface.

  • 16.
    Johnell, Matilda
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    The influence of different heparin surface concentrations and antithrombin-binding capacity on inflammation and coagulation2005In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 26, no 14, p. 1731-1739Article in journal (Refereed)
    Abstract [en]

    The corline heparin surface (CHS) used in the extracorporeal circuit during coronary artery bypass grafting is shown to decrease the activation of inflammation and coagulation. Synchrotron radiation studies have shown that a single layer of the CHS may not completely cover the substrate surface. However, a double layer of CHS results in a uniform surface. We investigated the effect of surfaces with different surface concentrations of heparin on cell activation and coagulation compared to an uncoated surface.

    The CHS is prepared by a conditioning layer of polymeric amine onto which a macromolecular heparin conjugate is attached. We used PVC tubing, uncoated or modified with a single or double layer of the CHS, and circulated fresh whole blood from healthy volunteers in a loop model system at 37°C up to 4 h. Blood was drawn from the loops at different times and activation of inflammation and coagulation was studied by real-time PCR, flow cytometry and ELISA. The activation of leukocytes and platelets and formation of leukocyte–platelet aggregates were reduced by use of the single-layered CHS compared to the uncoated surface. Use of double-layered CHS resulted in significantly reduced cell activation and thrombin generation. Development of the CHS obtained by the double layer of the coating has improved the biocompatibility of the surface.

  • 17.
    Karlsson, Marjam
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Surface Biotechnology.
    Pålsgård, Eva
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry, Surface Biotechnology, Centre for Surface Biotechnology.
    Wilshaw, Peter R
    Di Silvio, Lucy
    Initial in vitro interaction of osteoblasts with nano-porous alumina2003In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 24, no 18, p. 3039-3046Article in journal (Refereed)
    Abstract [en]

    In the present study we have used a characterised primary human cell culture model to investigate cellular interactions with nano-porous alumina. This material, prepared by anodisation, is being developed as a coating on titanium alloy implants. The structure of the alumina, as determined by X-ray diffraction and transmission electron microscopy, was amorphous. When studying cell/material interactions we used both biochemical and morphological parameters. Cell viability, proliferation and phenotype were assessed by measurement of redox reactions in the cells, cellular DNA, tritiated thymidine ([H-3]-TdR) incorporation and alkaline phosphatase (ALP) production. Results showed a normal osteoblastic growth pattern with increasing cell numbers during the first 2 weeks. A peak in cell proliferation was seen on day 3, after which cell growth decreased, followed by an increase in ALP production, thus indicating that the osteoblastic phenotype was retained on the alumina. Cell adhesion was observed, the osteoblast-like cells having a flattened morphology with filipodia attached to the pores of the material. SDS-PAGE and western blot measurements showed that the nano-porous alumina was able to adsorb fibronectin. Trace amounts of aluminium ions were measured in the surrounding medium, but no adverse effect on cell activity was observed.

  • 18. Kettenberger, Ulrike
    et al.
    Ston, Julien
    Thein, Eric
    Procter, Philip
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Pioletti, Dominique P.
    Does locally delivered Zoledronate influence pen-implant bone formation?: Spatio-temporal monitoring of bone remodeling in vivo2014In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 35, no 37, p. 9995-10006Article in journal (Refereed)
    Abstract [en]

    Bisphosphonates are known for their strong inhibitory effect on bone resorption. Their influence on bone formation however is less clear. In this study we investigated the spatio-temporal effect of locally delivered Zoledronate on pen-implant bone formation and resorption in an ovariectomized rat femoral model. A cross-linked hyaluronic acid hydrogel was loaded with the drug and applied bilaterally in predrilled holes before inserting polymer screws. Static and dynamic bone parameters were analyzed based on in vivo microCT scans performed first weekly and then biweekly. The results showed that the locally released Zoledronate boosted bone formation rate up to 100% during the first 17 days after implantation and reduced the bone resorption rate up to 1000% later on. This shift in bone remodeling resulted in an increase in bone volume fraction (BV/TV) by 300% close to the screw and 100% further away. The double effect on bone formation and resorption indicates a great potential of Zoledronateloaded hydrogel for enhancement of pen-implant bone volume which is directly linked to improved implant fixation.

  • 19.
    Kisiel, Marta
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Martino, Mikaël M.
    Ventura, Manuela
    Hubbell, Jeffrey A.
    Hilborn, Jöns
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Ossipov, Dmitri A.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Improving the osteogenic potential of BMP-2 with hyaluronic acid hydrogel modified with integrin-specific fibronectin fragment2013In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 34, no 3, p. 704-712Article in journal (Refereed)
    Abstract [en]

    While human bone morphogenetic protein-2 (rhBMP-2) is a promising growth factor for bone regeneration, its clinical efficacy has recently shown to be below expectation. In order to improve the clinical translation of rhBMP-2, there exists strong motivation to engineer better delivery systems. Hyaluronic acid (HA) hydrogel is a suitable carrier for the delivery of rhBMP-2, but a major limitation of this scaffold is its low cell adhesive properties. In this study, we have determined whether covalent grafting of an integrin-specific ligands into HA hydrogel could improve cell attachment and further enhance the osteogenic potential of rhBMP-2. A structurally stabilized fibronectin (FN) fragment containing the major integrin-binding domain of full-length FN (FN III9 *-10) was engineered, in order to be incorporated into HA hydrogel. Compared to non-functionalized HA hydrogel, HA-FN hydrogel remarkably improved the capacity of the material to support mesenchymal stem cell attachment and spreading. In an ectopic bone formation model in the rat, delivery of rhBMP-2 with HA-FN hydrogel resulted in the formation of twice as much bone with better organization of collagen fibers compared to delivering the growth factor in non-functionalized HA hydrogel. This engineered hydrogel carrier for rhBMP-2 can be relevant in clinical bone repair.

  • 20.
    Klapper, Yvonne
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Hamad, Osama A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Teramura, Yuji
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Leneweit, Gero
    Nienhaus, G. Ulrich
    Ricklin, Daniel
    Lambris, John D.
    Ekdahl, Kristina Nilsson
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Mediation of a non-proteolytic activation of complement component C3 by phospholipid vesicles2014In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 35, no 11, p. 3688-3696Article in journal (Refereed)
    Abstract [en]

    Liposomes are becoming increasingly important as drug delivery systems, to target a drug to specific cells and tissues and thereby protecting the recipient from toxic effects of the contained drug. Liposome preparations have been described to activate complement. In this study, we have investigated complement activation triggered by neutral dimyristoyl-phosphocholine (DMPC) liposomes in human plasma and whole-blood systems. Incubation in plasma led to the generation of complement activation products (C3a and sC5b-9). Unexpectedly, investigations of surface-bound C3 revealed contact activated, conformationally changed C3 molecules on the liposomes. These changes were characterized by Western blotting with C3 monoclonal antibodies, and by incubating liposomes with purified native C3 and factors I and H. Quartz crystal microbalance analysis confirmed binding of C3 to planar DMPC surfaces. In addition, we demonstrated that DMPC liposomes bound to or were phagocytized by granulocytes in a complement-dependent manner, as evidenced by the use of complement inhibitors. In summary, we have shown that C3 is activated both by convertase-dependent cleavage, preferentially in the fluid phase, by mechanisms which are not well elucidated, and also by contact activation into C3(H2O) on the DMPC surface. In particular, this contact activation has implications for the therapeutic regulation of complement activation during liposome treatment. (C) 2013 Elsevier Ltd. All rights reserved.

  • 21. Kloss, Frank
    et al.
    Gassner, Robert
    Preiner, Johannes
    Ebner, Andreas
    Larsson, Karin
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Materials Chemistry, Inorganic Chemistry.
    Hächl, Oliver
    Tuli, Tarkan
    Rasse, Michael
    Moser, Doris
    Laimer, Klaus
    Nickel, Eike
    Laschober, Gerhard
    Brunauer, Regina
    Klima, Günther
    Hinterdorfer, Peter
    Steinmüller-Nethl, Doris
    Lepperdinger, Günter
    The role of oxygen termination of nanocrystalline diamond on immobilisation of BMP-2 and subsequent bone formation2008In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 29, no 16, p. 2433-2442Article in journal (Refereed)
    Abstract [en]

    Medical implants are increasingly often inserted into bone of frail patients, who are advanced in years. Due to age, severe trauma or pathology-related bone changes, osseous healing at the implant site is frequently limited. We were able to demonstrate that coating of endosseous implants with nanocrystalline diamond (NCD) allows stable functionalization by means of physisorption with BMP-2. Strong physisorption was shown to be directly related to the unique properties of NCD, and BMP-2 in its active form interacted strongly when NCD was oxygen-terminated. The binding of the protein was monitored under physiological conditions by single molecule force spectroscopy, and the respective adsorption energies were further substantiated by force-field-calculations. Implant surfaces refined in such a manner yielded enhanced osseointegration in vivo, when inserted into sheep calvaria. Our results further suggest that this technical advancement can be readily applied in clinical therapies with regard to bone healing, since primary human mesenchymal stromal cells strongly activated the expression of osteogenic markers when being cultivated on NCD physisorbed with physiological amounts of BMP-2.

  • 22.
    Li, Hao
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Edin, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Hayashi, Hisamitsu
    Gifu Univ, Dept Otolaryngol, Gifu, Japan.
    Gudjonsson, Olafur
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Danckwardt-Lillieström, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Engqvist, Håkan
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Rask-Andersen, Helge
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Xia, Wei
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Guided Growth of Auditory Neurons: Bioactive Particles Towards Gapless Neural - Electrode Interface2017In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 122, p. 1-9Article in journal (Refereed)
    Abstract [en]

    Cochlear implant (CI) is a successful device to restore hearing. Despite continuous development, frequency discrimination is poor in CI users due to an anatomical gap between the auditory neurons and CI electrode causing current spread and unspecific neural stimulation. One strategy to close this anatomical gap is guiding the growth of neuron dendrites closer to CI electrodes through targeted slow release of neurotrophins. Biodegradable calcium phosphate hollow nanospheres (CPHSs) were produced and their capacity for uptake and release of neurotrophins investigated using I-125-conjugated glia cell line-derived neurotrophic factor (GDNF). The CPHSs were coated onto CI electrodes and loaded with neurotrophins. Axon guidance effect of slow-released neurotrophins from the CPHSs was studied in an in vitro 3D culture model. CPHS coating bound and released GDNF with an association rate constant 6.3 x 10(3) M(-1)s(-1) and dissociation rate 2.6 x 10(-5) s(-1), respectively. Neurites from human vestibulocochlear ganglion explants found and established physical contact with the GDNF-loaded CPHS coating on the CI electrodes placed 0.7 mm away. Our results suggest that neurotrophin delivery through CPHS coating is a plausible way to close the anatomical gap between auditory neurons and electrodes. By overcoming this gap, selective neural activation and the fine hearing for CI users become possible.

  • 23.
    Lindahl, Carl
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Engqvist, Håkan
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Xia, Wei
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Influence of surface treatments on the bioactivity of Ti2013In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 2013, p. 205601-Article in journal (Refereed)
    Abstract [en]

    Several techniques have been described to modify the surface of titanium to make it more bioactive. Heat treatment (HT) and sodium hydroxide treatment (NaOH) have been used and can change the crystallinity and surface chemistry of titanium implants. However, no studies have systemically focused on comparing these different methods and their effect on the bioactivity of Ti. Therefore, in this study, Ti substrates were systematically treated using HT, NaOH, and a combination of HT and NaOH. The Ti plates were heat treated at various temperatures, and the plates were subjected to HT followed by soaking in NaOH or first soaked in NaOH and then heat treated. The morphology, crystallinity, hardness, water contact angle, and surface energy of the samples were analyzed as well as the bioactivity after immersion in PBS. Morphology and crystallinity changed with increasing temperature. The difference was most pronounced for the 800°C treated samples. The water contact angle decreased, and the surface energy increased with increasing temperature and was highest for 800°C. The rutile surface showed faster hydroxyapatite formation. NaOH treatment of the HT Ti samples increased the surface energy and improved its bioactivity further. Also, HT of NaOH samples improved the bioactivity compared to only HT.

  • 24.
    Lindberg, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Heinrichs, Jannica
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Ericson, Fredric
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Microstructure Laboratory.
    Thomsen, Peter
    Engqvist, Håkan
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Hydroxylapatite growth on single-crystal rutile substrates2008In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 29, no 23, p. 3317-3323Article in journal (Refereed)
    Abstract [en]

    Titanium is widely used as an implant material. In addition to the bulk properties of titanium, the biological response is to a large degree controlled via the surface. The native amorphous titanium oxide that forms spontaneously on the surface gives a very good biological response. Lately it has been shown that crystalline titanium oxides (rutile and anatase) have in vitro bioactive properties. In addition to its potential for new materials development, this finding also opens up for the possibility of studying the mechanisms of bioactivity on materials with strictly controlled surfaces. In this paper the mechanisms behind the in vitro bioactivity are studied, using rutile single crystals. Three single-crystal rutile substrates: (100), (110), and (001), and a polycrystalline rutile substrate obtained by physical vapour deposition were soaked in a phosphate buffered saline solution for up to 4 weeks. The hydroxylapatite films that formed were analysed by X-ray diffraction, scanning electron microscopy, focused ion beam, and transmission electron microscopy. The hydroxylapatite grew faster on the (001) surface than on the other two. It was also found that on the (001) surface the direction of fast growth in hydroxylapatite was aligned parallel to the surface. This is in contrast to the (110) rutile surface where the fast growth of the hydroxylapatite crystal was directed outwards from the surface. The (100) face had poor adhesion at the interface. The orientations of the precipitated crystallites play a significant role in the faster coverage of the (001) rutile face. Based on the experimental results, a model for the hydroxylapatite growth process is given.

  • 25. Nejadnik, M. Reza
    et al.
    Yang, Xia
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Bongio, Mattilde
    Alghamdi, Hamdan S.
    van den Beucken, Jeroen J. J. P.
    Huysmans, Marie C.
    Jansen, John A.
    Hilborn, Jöns
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Ossipov, Dmitri
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Leeuwenburgh, Sander C. G.
    Self-healing Hybrid Nanocomposites consisting of Bisphosphonated Hyaluronan and Calcium Phosphate Nanoparticles2014In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 35, no 25, p. 6918-6929Article in journal (Refereed)
    Abstract [en]

    Non-covalent interactions are often regarded as insufficient to construct macroscopic materials of substantial integrity and cohesion. However, the low binding energy of such reversible interactions can be compensated by increasing their number to work in concert to create strong materials. Here we present the successful development of an injectable, cohesive nanocomposite hydrogel based on reversible bonds between calcium phosphate nanoparticles and bisphosphonate-functionalized hyaluronic acid. These nanocomposites display a capacity for self-healing as well as adhesiveness to mineral surfaces such as enamel and hydroxyapatite. Most importantly, these non-covalently cross-linked composites are surprisingly robust yet biodegradable upon extensive in vitro and in vivo testing and show bone interactive capacity evidenced by bone ingrowth into material remnants. The herein presented method provides a new methodology for constructing nanoscale composites for biomedical applications, which owe their integrity to reversible bonds.

  • 26. Nilsson, Per H.
    et al.
    Engberg, Anna E.
    Bäck, Jennie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Faxälv, Lars
    Lindahl, Tomas L.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Ekdahl, Kristina N.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    The creation of an antithrombotic surface by apyrase immobilization2010In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 31, no 16, p. 4484-4491Article in journal (Refereed)
    Abstract [en]

    Blood incompatibility reactions caused by surfaces often involve platelet activation and subsequent platelet-initiated activation of the coagulation and complement cascades. The goal of this study was to immobilize apyrase on a biomaterial surface in order to develop an enzymatically active surface that would have the capacity to inhibit platelet activation by degrading ADP. We were able to immobilize apyrase on a polystyrene surface with preservation of the enzymatic activity. We then analyzed the hemocompatibility of the apyrase surface and of control surfaces by incubation with platelet-rich plasma (PRP) or whole blood. Monitoring of markers of platelet, coagulation, and complement activation and staining of the surfaces revealed decreased levels of platelet and coagulation activation parameters on the apyrase surface. The formation of antithrombin-thrombin and antithrombin-factor XIa complexes and the extent of platelet consumption were significantly lower on the apyrase surface than on any of the control surfaces. No significant differences were seen in complement activation (C3a levels). Staining of the apyrase surface revealed low platelet adherence and no formation of granulocyte-platelet complexes. These results demonstrate that it is possible to create an antithrombotic surface targeting the ADP amplification of platelet activation by immobilizing apyrase.

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

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

  • 28. Pekna, M
    et al.
    Larsson, R
    Formgren, B
    Nilsson, U R
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Nilsson, B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Complement activation by polymethyl methacrylate minimized by end-point heparin attachment.1993In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 14, no 3, p. 189-192Article in journal (Refereed)
    Abstract [en]

    After intraocular lens implantation, despite good clinical results, many cataract patients develop a chronic uveitis, caused by an inflammatory response to the implant. One way to improve the biocompatibility of the intraocular lens is to modify the surface by end-point heparin attachment. This study shows that complement activation caused by poly(methyl methacrylate) can be diminished by end-point heparin attachment, as demonstrated by a significant reduction in the generation of C3a and fluid phase terminal complement complexes. It suggests that assessment of complement activation is a good indicator of the biocompatibility of intraocular lenses.

  • 29.
    Pujari-Palmer, Shiuli
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Chen, Song
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Rubino, Stefano
    Weng, Hong
    Xia, Wei
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Engqvist, Håkan
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Tang, Liping
    Ott, Marjam Karlsson
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    In vivo and in vitro evaluation of hydroxyapatite nanoparticle morphology on the acute inflammatory response2016In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 90, p. 1-11Article in journal (Refereed)
    Abstract [en]

    Biomedical implants have been widely used in bone repair applications. However, nanosized degradation products from these implants could elicit an inflammatory reaction, which may lead to implant failure. It is well known that the size, chemistry, and charge of these nanoparticles can modulate this response, but little is known regarding the role that the particle's morphology plays in inducing inflammation. The present study aims to investigate the effect of hydroxyapatite nanoparticle (HANPs) morphology on inflammation, in-vitro and in-vivo. Four distinct HANP morphologies were fabricated and characterized: long rods, dots, sheets, and fibers. Primary human polymorphonuclear cells (PMNCs), mononuclear cells (MNCs), and human dermal fibroblasts (hDFs) were exposed to HANPs and alterations in cell viability, morphology, apoptotic activity, and reactive oxygen species (ROS) production were evaluated, in vitro. PMNCs and hDFs experienced a 2-fold decrease in viability following exposure to fibers, while MNC viability decreased 5-fold after treatment with the dots. Additionally, the fibers stimulated an elevated ROS response in both PMNCs and MNCs, and the largest apoptotic behavior for all cell types. Furthermore, exposure to fibers and dots resulted in greater capsule thickness when implanted subcutaneously in mice. Collectively, these results suggest that nanoparticle morphology can significantly impact the inflammatory response.

  • 30. Ramstedt, M
    et al.
    Ekstrand-Hammarström, B B
    Shcukarev, A
    Welch, M
    Bucht, A
    Österlund, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Solid State Physics.
    Huck, Wilhelm T.S
    Bacterial and Mammalian Cell Response to Poly (3-Sulfopropyl methacrylate) Brushes Loaded with Silver Halide Salts2009In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 30, no 8, p. 1524-1531Article in journal (Refereed)
  • 31.
    Strand, Sabina P
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lelu, Sylvie
    Reitan, Nina K
    de Lange Davies, Catharina
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Vårum, Kjell M
    Molecular design of chitosan gene delivery systems with an optimized balance between polyplex stability and polyplex unpacking2010In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 31, no 5, p. 975-987Article in journal (Refereed)
    Abstract [en]

    Chitosan is an attractive gene delivery vehicle, but the criteria and strategies for the design of efficient chitosan gene delivery systems remain unclear. The purpose of this work was to investigate how the strength of the charge-based interaction between chitosan and DNA determines the gene expression levels and to design chitosan vectors with an optimized balance between polyplex stability and polyplex unpacking. Using 21 formulations based on low molecular weight chitosans with constant charge density and a number-average degree of polymerization (DPn) in the range of 21-88 (M(w) 4.7-33kDa), we studied the relationship between the chain length and the formulation properties, cellular uptake of polyplexes and gene transfer efficacy. We were able to identify a narrow interval of DPn31-42 that mediated the maximum level of transgene expression. An increase in chain length and/or the amino-phosphate (A/P) ratio reduced and delayed transgene expression. Compared to DPn31, transfection with the same amount of DPn72 or DPn88 resulted in 10-fold-lower expression levels. The gene transfer pattern correlated with the ability of heparin to release DNA from the polyplexes. As a tool to facilitate the unpacking of the polyplexes, we substituted the chitosans with uncharged oligosaccharides that reduced the interaction with DNA. The substitution of chitosans that originally yielded too stable polyplexes, such as DPn72 and DPn88 resulted in a 5-10-fold enhancement of the expression levels. However, the substitution of chitosans shorter than DP28 completely abolished transfection. Tailoring of the chain length and the substitution of chitosan were shown to be feasible tools to modulate the electrostatic interactions between the chitosan and DNA and to design chitosans with an optimized balance between polyplex stability and polyplex unpacking.

  • 32.
    Teramura, Yuji
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Podiyan, Oommen
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Olerud, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Hilborn, Jöns
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Microencapsulation of cells, including islets, within stable ultra-thin membranes of maleimide-conjugated PEG-lipid with multifunctional crosslinkers2013In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 34, no 11, p. 2683-2693Article in journal (Refereed)
    Abstract [en]

    The encapsulation of islets of Langerhans (islets) and insulin-secreting cells within a semi-permeable membrane has been suggested as a safe and simple technique for islet transplantation to attenuate early graft loss and avoid immunosuppressive therapy. The total volume of these implants tends, however, to increase upon encapsulation of the islets and cells within the polymer membrane, limiting transport between encapsulated cells and the surrounding tissue. Ultra-thin membranes could potentially overcome these diffusion limitations to provide for clinically applicable implants. Here we propose a method to encapsulate islets and cells within a stable ultra-thin polymer membrane using poly(ethylene glycol)-conjugated phospholipid bearing a maleimide group (Mal-PEG-lipids) and multiple interactive polymers (e.g., 4-arm PEG-Mal and 8-arm PEG-SH). When Mal-PEG-lipids were added to islet and cell suspensions, spontaneous incorporation into a cell surface occurred from the micelles at an equilibrium state. The addition of 4-arm PEG-Mal and 8-arm PEG-SH to the mixture induced a substantial increase in the membrane thickness because a number of Mal-PEG-lipid micelles were involved in the membrane formation at the micrometer level. No appreciable increase in islet volume was observed after microencapsulation by this method. Microencapsulation of islets with the polymer membranes, which showed semi-permeability, did not impair insulin release in response to glucose stimulation, even after 7 days. The polymer membrane structure surrounding the islets and cells was well maintained for at least 30 days. In addition, the membrane formed showed much lower thrombogenicity and inhibited complement activation upon exposure to human whole blood and serum.

  • 33.
    Thor, Andreas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Oral and Maxillofacial Surgery.
    Rasmusson, Lars
    Biomaterialvetenskap Göteborgs universitet.
    Wennerberg, Ann
    Biomaterialvetenskap Göteborgs universitet.
    Thomsen, Peter
    Biomaterialvetenskap Göteborgs universitet.
    Hirsch, Jan-Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Oral and Maxillofacial Surgery.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Hong, Jaan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    The role of whole blood in thrombin generation in contact with various titanium surfaces2007In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 28, no 6, p. 966-974Article in journal (Refereed)
    Abstract [en]

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

  • 34.
    Westerlund, Kristina
    et al.
    KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Dept Prot Sci, S-10691 Stockholm, Sweden.
    Vorobyeva, Anzhelika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Mitran, Bogdan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Karlström, Amelie Eriksson
    KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Dept Prot Sci, S-10691 Stockholm, Sweden.
    Altai, Mohamed
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Site-specific conjugation of recognition tags to trastuzumab for peptide nucleic acid-mediated radionuclide HER2 pretargeting2019In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 203, p. 73-85Article in journal (Refereed)
    Abstract [en]

    Pretargeting is a promising strategy to reach high imaging contrast in a shorter time than by targeting with directly radiolabeled monoclonal antibodies (mAbs). One of problems in pretargeting is a site-specific, reproducible and uniform conjugation of recognition tags to mAbs. To solve this issue we propose a photoconjugation to covalently couple a recognition tag to a mAb via a photoactivatable Z domain. The Z-domain, a 58-amino acid protein derived from the IgG-binding B-domain of Staphylococcus aureus protein A, has a well-characterized binding site in the Fc portion of IgG. We tested the feasibility of this approach using pretargeting based on hybridization between peptide nucleic acids (PNAs). We have used photoconjugation to couple trastuzumab with the PNA-based hybridization probe, HP1. A complementary [Co-57]Co-labeled PNA hybridization probe ([Co-57]Co-HP2) was used as the secondary targeting probe. In vitro studies demonstrated that trastuzumab-ZHP1 bound specifically to human epidermal growth factor receptor 2 (HER2)-expressing cells with nanomolar affinity. The binding of the secondary [Co-57]Co-HP2 probe to trastuzumab-PNA-pretreated cells was in the picomolar affinity range. A two-fold increase in SKOV-3 tumor targeting was achieved when [Co-57]Co-HP2 (0.7 nmol) was injected 48 h after injection of trastuzumab-ZHP1 (0.5 nmol) compared with trastuzumab-ZHP1 alone (0.8 +/- 0.2 vs. 0.33 +/- 0.06 %ID/g). Tumor accumulation of [Co-57]Co-HP2 was significantly reduced by pre-saturation with trastuzumab or when no trastuzumab-ZHP1 was preinjected. A tumor-to-blood uptake ratio of 1.5 +/- 0.3 was achieved resulting in a clear visualization of HER2-expressing xenografts as confirmed by SPECT imaging. In conclusion, the feasibility of stable site-specific coupling of a PNA-based recognition tag to trastuzumab and successful pretargeting has been demonstrated. This approach can hopefully be used for a broad range of mAbs and recognition tags.

  • 35. Widhe, Mona
    et al.
    Bysell, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Nystedt, Sara
    Schenning, Ingrid
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Johansson, Jan
    Rising, Anna
    Hedhammar, My
    Recombinant spider silk as matrices for cell culture2010In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 31, no 36, p. 9575-9585Article in journal (Refereed)
    Abstract [en]

    The recombinant miniature spider silk protein, 4RepCT, was used to fabricate film, foam, fiber and mesh matrices of different dimensionality, microstructure and nanotopography. These matrices were evaluated regarding their suitability for cell culturing. Human primary fibroblasts attached to and grew well on all matrix types, also in the absence of serum proteins or other animal-derived additives. The highest cell counts were obtained on matrices combining film and fiber/mesh. The cells showed an elongated shape that followed the structure of the matrices and exhibited prominent actin filaments. Moreover, the fibroblasts produced, secreted and deposited collagen type I onto the matrices. These results, together with findings of the matrices being mechanically robust, hold promise not only for in vitro cell culturing, but also for tissue engineering applications.

  • 36.
    Yan, Hongji
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Casalini, Tommaso
    Hulsart Billström, Gry
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Wang, Shujiang
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Oommen, Oommen P.
    Salvalaglio, Matteo
    Larsson, Sune
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Hilborn, Jöns
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Varghese, Oommen P.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Synthetic design of growth factor sequestering extracellular matrix mimetic hydrogel for promoting in vivo bone formation2018In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 161, p. 190-202Article in journal (Refereed)
    Abstract [en]

    Synthetic scaffolds that possess an intrinsic capability to protect and sequester sensitive growth factors is a primary requisite for developing successful tissue engineering strategies. Growth factors such as recombinant human bone morphogenetic protein-2 (rhBMP-2) is highly susceptible to premature degradation and to provide a meaningful clinical outcome require high doses that can cause serious side effects. We discovered a unique strategy to stabilize and sequester rhBMP-2 by enhancing its molecular interactions with hyaluronic acid (HA), an extracellular matrix (ECM) component. We found that by tuning the initial protonation state of carboxylic acid residues of HA in a covalently crosslinked hydrogel modulate BMP-2 release at physiological pH by minimizing the electrostatic repulsion and maximizing the Van der Waals interactions. At neutral pH, BMP-2 release is primarily governed by Fickian diffusion, whereas at acidic pH both diffusion and electrostatic interactions between HA and BMP-2 become important as confirmed by molecular dynamics simulations. Our results were also validated in an in vivo rat ectopic model with rhBMP-2 loaded hydrogels, which demonstrated superior bone formation with acidic hydrogel as compared to the neutral counterpart. We believe this study provides new insight on growth factor stabilization and highlights the therapeutic potential of engineered matrices for rhBMP-2 delivery and may help to curtail the adverse side effects associated with the high dose of the growth factor.

  • 37.
    Yanlun, Zhu
    et al.
    Shanghai Jiao Tong University, China.
    Lingzhi, Kong
    Shanghai Jiao Tong University, China.
    Fatemeh, Farhadi
    Shanghai Jiao Tong University, China.
    Xia, Wei
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Chang, Jiang
    Shanghai Institute of ceramics, Chinese academy of sciences, China.
    Yaohua, He
    Shanghai Jiao Tong University, China.
    Haiyan, Li
    Shanghai Jiao Tong University, China.
    An injectable continuous stratified structurally and functionally biomimetic construct for enhancing osteochondral regeneration2018In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 192, p. 149-158Article in journal (Refereed)
    Abstract [en]

    Osteochondral regeneration with the formation of hyaline cartilage and subchondral bone as well as the integration between the newly formed tissues with the host tissue still remains a great challenge. In this study, a construct containing an injectable continuous stratified scaffold and multiple cell systems was designed for enhancing osteochondral regeneration. Briefly, an injectable sodium alginate(SA)/bioglass (BG) composite hydrogel containing bone marrow stem cells (BMSCs) (SA/BG + BMSCs) was used for subchondral bone regeneration and an injectable thermosensitive SA/agarose (AG) composite hydrogel with co-culture of BMSCs and articular chondrocytes (ACs) (SA/AG + ACs/BMSCs) was applied for articular cartilage regeneration. The continuous SA phase and the stratified structure enable the scaffold to mimic the natural osteochondral structure. In addition, the SA/BG + BMSCs hydrogel could enhance the osteoblast differentiation of BMSCs by upregulating their alkaline phosphatase and collagen I gene expressions, and the SA/AG + ACs/BMSCs hydrogel could promote the chondrocyte differentiation of BMSCs by upregulating their Acan and collagen II gene expressions, which indicated that this stratified scaffold could mimic the natural osteochondral function. Furthermore, after the stratified construct was injected into a rat osteochondral defect model, obvious neonatal articular cartilage tissues and subchondral bone tissues with regular surface and highly integration with normal tissues could be observed. This structural and functional biomimetic construct, together with its proper swelling ratio, could not only stimulate the hyaline cartilage and subchondral bone regeneration in an entire osteochondral unit but also promote the integration between the newly formed tissues and the host tissue.

1 - 37 of 37
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