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  • 1.
    Asplund, J. O. Basse
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Materials Chemistry.
    Bowden, Tim
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Materials Chemistry.
    Mathisen, Torbjörn
    Hilborn, Jöns
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Materials Chemistry.
    Synthesis of highly elastic biodegradable poly(urethane urea)2007In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 8, no 3, p. 905-911Article in journal (Refereed)
    Abstract [en]

    Linear poly(urethane urea) containing a biodegradable soft segment and a hard segment built solely from methyl-2,6-diisocyanatehexanoate (LDI) is presented, using a procedure where no chain extender is required. By having LDI in excess, together with a soft segment, and adding water in the vapor phase continuously creates amines in situ resulting in hard segments containing multiple LDI units linked via urea linkages. As soft segments, polymers of trimethylene carbonate (TMC) and copolymers of TMC, ε-caprolactone, and d,l-lactic acid (DLLA) were used. High inherent viscosity, 0.95−1.65 dL/g, was afforded even when DLLA-containing soft segments were used, which usually undergo aminolysis. With a hard segment content between 12% and 18%, all of the materials showed very high elongation at breakage, ranging from 1600% to 4700%, and an elastic modulus from 2.1 to 140 MPa. This one-pot synthesis is simple and has now been shown to be applicable to a large number of systems.

  • 2.
    Atthoff, Björn
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Materials Chemistry, Polymer Chemistry.
    Nederberg, Fredrik
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Materials Chemistry, Polymer Chemistry.
    Söderberg, Lennart
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Surface Biotechnology.
    Hilborn, Jöns
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Materials Chemistry, Polymer Chemistry.
    Bowden, Tim
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Materials Chemistry, Polymer Chemistry.
    Synthetic Biodegradable Ionomers that Engulf, Store, and Deliver Intact Proteins2006In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 7, no 8, p. 2401-2406Article in journal (Refereed)
    Abstract [en]

    Telechelic anionic and cationic biodegradable ionomers capable of loading, storing, and releasing proteins are presented. Two different ionomers have been synthesized with either anionic or cationic end groups. The reaction was done quantitatively as shown by 1H NMR. The swelling properties of the hydrophobic poly(trimethylene carbonate) polymer are contributed to the ionic end groups that display hydrophilic properties. Depending on the molecular weight of the ionomer, and also on the ionic charge, the materials swell differently in water, from ~50% for Mw = 12 000 g/mol to ~500% when dealing with 2000 g/mol. The high swelling led us to believe that it would be possible to load and release proteins preferably in a still active form. As models, two different proteins were chosen: hemoglobin and cytochrome c. The swelling and release study shows that both ionomers possess the capability to adsorb and later release the proteins with retained structure. Release measurements from both the swollen and dried states have been evaluated with similar results, showing that the dried state seems to release a little bit less than the swollen one. These kinds of materials should be interesting for a wide variety of applications where drug and protein release is wanted, as well as in applications such as protein separation media.

  • 3.
    Bergman, Kristoffer
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Materials Chemistry.
    Elvingson, Christer
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry.
    Hilborn, Jöns
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Materials Chemistry.
    Svensk, Göran
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry.
    Bowden, Tim
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Materials Chemistry.
    Hyaluronic acid derivatives prepared in aqueous media by triazine-activated amidation2007In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 8, no 7, p. 2190-2195Article in journal (Refereed)
    Abstract [en]

    A method is presented for the preparation of hyaluronic acid derivatives obtained through triazine-activated amidation. A number of amines were successfully reacted with hyaluronic acid carboxyl groups using 2-chloro-4,6-dimethoxy-1,3,5-triazine as an activating species in a mixture of water and acetonitrile under neutral conditions. By varying the amount of triazine reagent, it was possible to control the degree of modification. Depending on the amine chosen, degrees of modification ranging from 3 to 20% were obtained when using 0.5 equiv of the triazine to hyaluronic acid carboxyl groups. The possibility to perform the reaction in a mixture of water and acetonitrile facilitates the introduction of a wide range of both hydrophilic and hydrophobic amines. Triazine-activated amidation appears to be a highly versatile, controllable, and relatively mild technique for modification of hyaluronic acid, and we predict that it will be useful in the design of novel hyaluronic acid based biomaterials.

  • 4.
    Bermejo-Velasco, Daniel
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Azémar, Alice
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Oommen, Oommen P.
    Bioengineering and Nanomedicine Lab, Faculty of Medicine and Health Technologies and BioMediTech Institute, Tampere University, Korkeakoulunkatu 3, Tampere 33720, Finland.
    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.
    Modulating thiol pKa promotes disulfide formation at physiological pH: An elegant strategy to design disulfide cross-linked hyaluronic acid hydrogels2019In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 20, no 3, p. 1412-1420Article in journal (Refereed)
    Abstract [en]

    The disulfide bond plays a crucial role in protein biology and has been exploited by scientists to develop antibody-drug conjugates, sensors and for the immobilization other biomolecules to materials surfaces. In spite of its versatile use, the disulfide chemistry suffers from some inevitable limitations such as the need for basic conditions (pH > 8.5), strong oxidants and long reaction times. We demonstrate here that thiol-substrates containing electron-withdrawing groups at the β-position influence the deprotonation of the thiol group, which is the key reaction intermediate in the formation of disulfide bonds. Evaluation of reaction kinetics using small molecule substrate such as L-cysteine indicated disulfide formation at a 2.8-fold higher (k1 = 5.04 x 10-4 min-1) reaction rate as compared to the conventional thiol substrate, namely 3-mercaptopropionic acid (k1 = 1.80 x 10-4 min-1) at physiological pH (pH 7.4). Interestingly, the same effect could not be observed when N-acetyl-L-cysteine substrate (k1 = 0.51 x 10-4 min-1) was used. We further grafted such thiol-containing molecules (cysteine, N-acetyl-cysteine, and 3-mercaptopropionic acid) to a biopolymer namely hyaluronic acid (HA) and determined the pKa value of different thiol groups by spectrophotometric analysis. The electron-withdrawing group at the β-position reduced the pKa of the thiol group to 7.0 for HA-cysteine (HA-Cys); 7.4 for N-acetyl cysteine (HA-ActCys) and 8.1 for HA-thiol (HA-SH) derivatives respectively. These experiments further confirmed that the concentration of thiolate (R-S-) ions could be increased with the presence of electron-withdrawing groups, which could facilitate disulfide cross-linked hydrogel formation at physiological pH. Indeed, HA grafted with cysteine or N-acetyl groups formed hydrogels within 3.5 minutes or 10 hours, respectively at pH 7.4. After completion of crosslinking reaction both gels demonstrated a storage modulus G’ ≈3300–3500 Pa, indicating comparable levels of crosslinking. The HA-SH gel, on the other hand, did not form any gel at pH 7.4 even after 24 h. Finally, we demonstrated that the newly prepared hydrogels exhibited excellent hydrolytic stability but can be degraded by cell-directed processes (enzymatic and reductive degradation). We believe our study provides a valuable insight on the factors governing the disulfide formation and our results are useful to develop strategies that would facilitate generation of stable thiol functionalized biomolecules or promote fast thiol oxidation according to the biomedical needs.

  • 5.
    Bjurhager, Ingela
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Mechanics.
    Halonen, Helena
    Wallenberg Wood Science Center, KTH, Stockholm.
    Lindfors, Eva-Lisa
    Innventia AB, Stockholm.
    Iversen, Tommy
    Wallenberg Wood Science Center, KTH, Stockholm.
    Almkvist, Gunnar
    Dept of Chemistry, SLU, Uppsala.
    Gamstedt, E. Kristofer
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Mechanics.
    Berglund, Lars A.
    Wallenberg Wood Science Center, KTH, Stockholm.
    State of Degradation in Archeological Oak from the 17th Century Vasa Ship: Substantial Strength Loss Correlates with Reduction in (Holo)Cellulose Molecular Weight2012In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 13, no 8, p. 2521-2527Article in journal (Refereed)
    Abstract [en]

    In 1628, the Swedish warship Vasa capsized on her maiden voyage and sank in the Stockholm harbor. The ship was recovered in 1961 and, after polyethylene glycol (PEG) impregnation, it was displayed in the Vasa museum. Chemical investigations of the Vasa were undertaken in 2000, and extensive holocellulose degradation was reported at numerous locations in the hull. We have now studied the longitudinal tensile strength of Vasa oak as a function of distance from the surface. The PEG-content, wood density, and cellulose microfibril angle were determined. The molar mass distribution of holocellulose was determined as well as the acid and iron content. A good correlation was found between the tensile strength of the Vasa oak and the average molecular weight of the holocellulose, where the load bearing cellulose microfibril is the critical constituent The mean, tensile strength is reduced by approximately 40%, and the most affected areas show a reduction of up to 80%. A methodology is,, developed where variations in density, cellulose microfibril angle, and PEG content are taken into account, so that. cell wall effects can be evaluated in wood samples with different rate of impregnation and morphologies.

  • 6.
    Bysell, Helena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Schmidtchen, Artur
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Binding and release of consensus peptides by poly(acrylic acid) microgels2009In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 10, no 8, p. 2162-2168Article in journal (Refereed)
    Abstract [en]

    The interaction between positively charged consensus peptides and  poly(acrylic acid) microgels was investigated with   micromanipulator-assisted light microscopy and confocal laser scanning   microscopy. Peptide binding and release was monitored by microgel   deswelling and swelling for monodisperse multiples of heparin-binding  Cardin and Weintraub motifs, (AKKARA)(n) (1 <= n <= 4) and   (ARKKAAKA)(n) (1 <= n <= 3), as well as the corresponding titratable   (AHHAHA)(4) and (AHHHAAHA)(3) peptides (A, K. R and H, refering to   alanine, lysine, arginine, and histidine, respectively). When fully   charged, these peptides distribute homogenously throughout the   microgels and display concentration-dependent deswelling, which   increases with increasing peptide length. Both (AKKARA)(4) and   (ARKKAAKA)(3) display potent and fast microgel deswelling but only   marginal subsequent electrolyte-induced desorption. In contrast,   reducing the peptide charge for (AHHAHA)(4) and (AHHHAAHA)(3) at  neutral and high pH, or the peptide length, substantially reduces the   peptide affinity for the microgels and facilitates rapid peptide release. Taken together, the results also show that quite short   peptides of moderate charge density interact strongly and cause   extensive gel deswelling of oppositely charged microgels, precluding   peptide release. They also show, however, that desirable triggered   release can be achieved with peptides of lower charge density.

  • 7. Cardenas, M.
    et al.
    Arnebrant, T.
    Rennie, Adrian
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Materials Science, Materials Physics.
    Fragneto, G.
    Thomas, R. K.
    Lindh, L.
    Human Saliva Forms a Complex Film Structure on Alumina Surfaces2007In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 8, no 1, p. 65-69Article in journal (Refereed)
    Abstract [en]

    Films formed from saliva on surfaces are important for the maintenance of oral health and integrity by protection against chemical and/or biological agents. The aim of the present study was to investigate adsorbed amounts, thickness, and structure of films formed from human whole saliva on alumina surfaces by means of in situ ellipsometry, neutron reflectivity, and atomic force microscopy. Alumina (Al2O3, synthetic sapphire) is a relevant and interesting substrate for saliva adsorption studies as it has an isoelectric point close to that of tooth enamel. The results showed that saliva adsorbs rapidly on alumina. The film could be modeled in two layers:  an inner and dense thin region that forms a uniform layer and an outer, more diffuse and thicker region that protrudes toward the bulk of the solution. The film morphology described a uniformly covering dense layer and a second outer layer containing polydisperse adsorbed macromolecules or aggregates.

  • 8.
    Carlsson, Daniel O
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Lindh, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Strømme, Maria
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Mihranyan, Albert
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Susceptibility of Iα- and Iβ-Dominated Cellulose to TEMPO-Mediated Oxidation2015In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 16, no 5, p. 1643-1649Article in journal (Refereed)
  • 9. Filonova, Lada
    et al.
    Kallas, Åsa
    Greffe, Lionel
    Johansson, Gunnar
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    Teeri, Tuula
    Daniel, Geoffrey
    Analysis of the Surfaces of Wood Tissues and Pulp Fibers Using Carbohydrate-Binding Modules Specific for Crystalline Cellulose and Mannan2007In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 8, p. 91-97Article in journal (Refereed)
  • 10.
    Filonova, Lada
    et al.
    Institutionen för skogens produkter, trävetenskap, Sveriges lantbruksuniversitet.
    Kallas, Åsa M.
    Greffe, Lionel
    Johansson, Gunnar
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Teeri, Tuula T.
    Daniel, Geoffrey
    Institutionen för skogens produkter, trävetenskap, Sveriges lantbruksuniversitet.
    Analysis of the Surfaces of Wood Tissues and Pulp Fibers Using Carbohydrate-Binding Modules Specific for Crystalline Cellulose and Mannan2007In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 8, no 1, p. 91-97Article in journal (Refereed)
    Abstract [en]

    Carbohydrate binding modules (CBMs) are noncatalytic substrate binding domains of many enzymes involved in carbohydrate metabolism. Here we used fluorescent labeled recombinant CBMs specific for crystalline cellulose (CBM1HjCel7A) and mannans (CBM27TmMan5 and CBM35CjMan5C) to analyze the complex surfaces of wood tissues and pulp fibers. The crystalline cellulose CBM1HjCel7A was found as a reliable marker of both bacterially produced and plant G-layer cellulose, and labeling of spruce pulp fibers with CBM1HjCel7A revealed a signal that increased with degree of fiber damage. The mannan-specific CBM27TmMan5 and CBM35CjMan5C CBMs were found to be more specific reagents than a monoclonal antibody specific for (1→4)-β-mannan/galacto-(1→4)-β-mannan for mapping carbohydrates on native substrates. We have developed a quantitative fluorometric method for analysis of crystalline cellulose accumulation on fiber surfaces and shown a quantitative difference in crystalline cellulose binding sites in differently processed pulp fibers. Our results indicated that CBMs provide useful, novel tools for monitoring changes in carbohydrate content of nonuniform substrate surfaces, for example, during wood or pulping processes and possibly fiber biosynthesis.

  • 11.
    Hua, Kai
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Rocha, Igor
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials. Minist Educ Brazil, CAPES Fdn, BR-70040020 Brasilia, DF, Brazil.
    Zhang, Peng
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Gustafsson, Simon
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Ning, Yi
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Strømme, Maria
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Mihranyan, Albert
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Ferraz, Natalia
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Transition from bioinert to bioactive material by tailoring the biological cell response to carboxylated nanocellulose2016In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 17, no 3, p. 1224-1233Article in journal (Refereed)
    Abstract [en]

    This work presents an insight into the relationship between cell response and physicochemical properties of Cladophora cellulose (CC) by investigating the effect of CC functional group density on the response of model cell lines. CC was carboxylated by electrochemical TEMPO-mediated oxidation. By varying the amount of charge passed through the electrolysis setup, CC materials with different degrees of oxidation were obtained. The effect of carboxyl group density on the material’s physicochemical properties was investigated together with the response of human dermal fibroblasts (hDF) and human osteoblastic cells (Saos-2) to the carboxylated CC films. The introduction of carboxyl groups resulted in CC films with decreased specific surface area and smaller total pore volume compared with the unmodified CC (u-CC). While u-CC films presented a porous network of randomly oriented fibers, a compact and aligned fiber pattern was depicted for the carboxylated-CC films. The decrease in surface area and total pore volume, and the orientation and aggregation of the fibers tended to augment parallel to the increase in the carboxyl group density. hDF and Saos-2 cells presented poor cell adhesion and spreading on u-CC, which gradually increased for the carboxylated CC as the degree of oxidation increased. It was found that a threshold value in carboxyl group density needs be reached to obtain a carboxylated-CC film with cytocompatibility comparable to commercial tissue culture material. Hence, this study demonstrates that a normally bioinert nanomaterial can be rendered bioactive by carefully tuning the density of charged groups on the material surface, a finding that not only may contribute to the fundamental understanding of biointerface phenomena, but also to the development of bioinert/bioactive materials.

  • 12.
    Hua, Kai
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Ålander, Eva
    Lindström, Tom
    Mihranyan, Albert
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Strömme, Maria
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Ferraz, Natalia
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Surface Chemistry of Nanocellulose Fibers Directs Monocyte/Macrophage Response2015In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 16, no 9, p. 2787-2795Article in journal (Refereed)
    Abstract [en]

    The effect of surface functionalization of nanofibrillated cellulose (NFC) on monocyte/macrophage (MM) behavior is investigated to understand how the physicochemical properties of nanocelluloses influence the interactions of such materials with biological systems. Films of anionic (a-), cationic (c-), and unmodified (u-) NFC were synthesized and characterized in terms of surface charge. THP-1 monocytes were cultured on the surface of the films for 24 h in the presence and absence of lipopolysaccharide, and the cell response was evaluated in terms of cell adhesion, morphology, and secretion of TNF-α, IL-10, and IL-1ra. The results show that MMs cultured on carboxymethylated-NFC films (a-NFC) are activated toward a proinflammatory phenotype, whereas u-NFC promotes a mild activation of the studied cells. The presence of hydroxypropyltrimethylammonium groups on c-NFC, however, does not promote the activation of MMs, indicating that c-NFC closely behaves as an inert material in terms of MM activation. None of the materials is able to directly activate the MMs toward an anti-inflammatory response. These results may provide a foundation for the design of future NFC-based materials with the ability to control MM activation and may expand the use of NFC in biomedical applications.

  • 13.
    Hulsart-Billström, Gry
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Yuen, Pik Kwan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Marsell, Richard
    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.
    Larsson, Sune
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Ossipov, Dmitri
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Bisphosphonate-Linked Hyaluronic Acid Hydrogel Sequesters and Enzymatically Releases Active Bone Morphogenetic Protein-2 for Induction of Osteogenic Differentiation2013In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 14, no 9, p. 3055-3063Article in journal (Refereed)
    Abstract [en]

    Regeneration of bone by delivery of bone morphogenetic proteins (BMPs) from implantable scaffolds is a promising alternative to the existing autologous bone grafting procedures. Hydrogels are used extensively in biomaterials as delivery systems for different growth factors. However, a controlled release of the growth factors is necessary to induce bone formation, which can be accomplished by various chemical functionalities. Herein we demonstrate that functionalization of a hyaluronan (HA) hydrogel with covalently linked bisphosphonate (BP) ligands provides efficient sequestering of BMP-2 in the resulting HA-BP hydrogel. The HA-BP hydrogel was investigated in comparison with its analogue lacking BP groups (HA hydrogel). While HA hydrogel released 100% of BMP-2 over two weeks, less than 10% of BMP-2 was released from the HA-BP hydrogel for the same time. We demonstrate that the sequestered growth factor can still be released by enzymatic degradation of the HA-BP hydrogel. Most importantly, entrapment of BMP-2 in HA-BP hydrogel preserves the growth factor bioactivity, which was confirmed by induction of osteogenic differentiation of mesenchymal stem cells (MSCs) after the cells incubation with the enzymatic digest of the hydrogel. At the same time, the hydrogels degradation products were not toxic to MSCs and osteoblasts. Furthermore, BP-functionalization of HA hydrogels promotes adhesion of the cells to the surface of HA hydrogel. Altogether, the present findings indicate that covalent grafting of HA hydrogel with BP groups can alter the clinical effects of BMPs in bone tissue regeneration.

  • 14.
    Karlsson, Rose-Marie Pernilla
    et al.
    KTH Royal Inst Technol, Wallenberg Wood Sci Ctr, Dept Fiber & Polymer Technol, Teknikringen 56, S-10044 Stockholm, Sweden.
    Larsson, Per Tomas
    KTH Royal Inst Technol, Wallenberg Wood Sci Ctr, Dept Fiber & Polymer Technol, Teknikringen 56, S-10044 Stockholm, Sweden;RISE Bioecon, Box 5604, S-11486 Stockholm, Sweden.
    Hansson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Wågberg, Lars
    KTH Royal Inst Technol, Wallenberg Wood Sci Ctr, Dept Fiber & Polymer Technol, Teknikringen 56, S-10044 Stockholm, Sweden;KTH Royal Inst Technol, Div Fibre Technol, Dept Fiber & Polymer Technol, Teknikringen 56, S-10044 Stockholm, Sweden.
    Thermodynamics of the Water-Retaining Properties of Cellulose-Based Networks2019In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 20, no 4, p. 1603-1612Article in journal (Refereed)
    Abstract [en]

    Noncrystalline cellulose-based gel beads were used as a model material to investigate the effect of osmotic stress on a cellulosic network. The gel beads were exposed to osmotic stress by immersion in solutions with different concentrations of high molecular mass dextran and the equilibrium dimensional change of the gel beads was studied using optical microscopy. The volume fraction of cellulose was calculated from the volume of the gel beads in dextran solutions and their dry content and the relation between the cellulose volume fraction and the total osmotic pressure was thus obtained. The results show that the contribution to the osmotic pressure from counterions increases the water-retaining capacity of the beads at high osmotic pressures but also that the main factor controlling the gel bead collapse at high osmotic strains is the resistance to the deformation of the polymer chain network within the beads. Furthermore, the osmotic pressure associated with the deformation of the polymer network, which counteracts the deswelling of the beads, could be fitted to the Wall model indicating that the response of the cellulose polymer networks was independent of the charge of the cellulose. The best fit to the Wall model was obtained when the Flory-Huggins interaction parameter (chi) of the cellulose-water system was set to 0.55-0.60, in agreement with the well-established insolubility of high molecular mass beta-(1,4)-D-glucan polymers in water.

  • 15.
    Kishani, Saina
    et al.
    Royal Inst Technol, Sch Chem Sci & Engn Fibre & Polymer Technol, Teknikringen 56-58, SE-10044 Stockholm, Sweden;Wallenberg Wood Sci Ctr WWSC, Teknikringen 56-58, SE-10044 Stockholm, Sweden.
    Escalante, Alfredo
    Univ Guadalajara, Wood Cellulose & Paper Res Dept, Guadalajara, Jalisco, Mexico.
    Toriz, Guillermo
    Univ Guadalajara, Wood Cellulose & Paper Res Dept, Guadalajara, Jalisco, Mexico;Chalmers Univ Technol, WWSC, Gothenburg, Sweden.
    Vilaplana, Francisco
    Wallenberg Wood Sci Ctr WWSC, Teknikringen 56-58, SE-10044 Stockholm, Sweden;Albanova Univ Ctr, Royal Inst Technol, Div Glycosci, Sch Biotechnol, SE-10691 Stockholm, Sweden.
    Gatenholm, Paul
    Chalmers Univ Technol, Chem Biol Engn Biopolymer, Gothenburg, Sweden;Chalmers Univ Technol, WWSC, Gothenburg, Sweden.
    Hansson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Wagberg, Lars
    Royal Inst Technol, Sch Chem Sci & Engn Fibre & Polymer Technol, Teknikringen 56-58, SE-10044 Stockholm, Sweden;Wallenberg Wood Sci Ctr WWSC, Teknikringen 56-58, SE-10044 Stockholm, Sweden.
    Experimental and Theoretical Evaluation of the Solubility/Insolubility of Spruce Xylan (Arabino Glucuronoxylan)2019In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 20, no 3, p. 1263-1270Article in journal (Refereed)
    Abstract [en]

    The molecular solubility of softwood arabinoglucuronoxylan (AGX) has been thoroughly investigated, and it has been shown that the chemical and physical structures of the extracted hemicellulose are not significantly influenced by different purification steps, but a transient molecular solubility of AGX was observed in aqueous media at low concentrations (1 g/L) when the dissolved macromolecules had a hydrodynamic diameter of up to 10 nm. A phase separation was detected when the concentration was increased to 15 g/L leading to an association of the smaller molecules into fractal structures with a considerably larger diameter, even though the dispersions were still transparent to ocular inspection. Dynamic Light Scattering and Cryo-Transmission Electron Microscopy showed dimensions in the range of 1000 nm. The phase separation of the sample was further characterized by estimating the chi-interaction parameter of AGX in water using the Flory Huggins theory, and the results supported that water is a poor solvent for AGX. This behavior is crucial when films and hydrogels based on these biopolymers are made, since the association will dramatically affect barrier and mechanical properties of films made from these materials.

  • 16. Kishani, Saina
    et al.
    Vilaplana, Francisco
    Ruda, Marcus
    Hansson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Wågberg, Lars
    Influence of Solubility on the Adsorption of Different Xyloglucan Fractions at Cellulose–Water Interfaces2019In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602Article in journal (Refereed)
  • 17.
    Kootala, Sujit
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry. UPPA, France.
    Chitin Nanoforms Provide Mechanical and Topological Cues to Support Growth of Human Adipose Stem Cells in Chitosan Matrices2018In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602Article in journal (Refereed)
  • 18.
    Kootala, Sujit
    et al.
    KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Dept Chem, Div Glycosci, Stockholm, Sweden.
    Filho, Luimar
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Srivastava, Vaibhav
    KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Dept Chem, Div Glycosci, Stockholm, Sweden.
    Linderberg, Victoria
    KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Dept Chem, Div Glycosci, Stockholm, Sweden.
    Moussa, Amani
    Univ Claude Bernard Lyon 1, Univ Lyon, CNRS UMR 5223, IMP, Villeurbanne, France.
    David, Laurent
    Univ Claude Bernard Lyon 1, Univ Lyon, CNRS UMR 5223, IMP, Villeurbanne, France.
    Trombotto, Stephane
    Univ Claude Bernard Lyon 1, Univ Lyon, CNRS UMR 5223, IMP, Villeurbanne, France.
    Crouzier, Thomas
    KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Dept Chem, Div Glycosci, Stockholm, Sweden.
    Reinforcing Mucus Barrier Properties with Low Molar Mass Chitosans2018In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 19, no 3, p. 872-882Article in journal (Refereed)
    Abstract [en]

    The mucus gel covers the wet epithelia that forms the inner lining of the body. It constitutes our first line of defense protecting the body from infections and other deleterious molecules. Failure of the mucus barrier can lead to the inflammation of the mucosa such as in inflammatory bowel diseases. Unfortunately, there are no effective strategies that reinforce the mucus barrier properties to recover or enhance its ability to protect the epithelium. Herein, we describe a mucus engineering approach that addresses this issue where we physically cross-link the mucus gel with low molar mass chitosan variants to reinforce its barrier functions. We tested the effect of these chitosans on mucus using in-lab purified porcine gastric mucins, which mimic the native properties of mucus, and on mucus-secreting HT29-MTX epithelial cell cultures. We found that the lowest molar mass chitosan variant (degree of polymerization of 8) diffuses deep into the mucus gels while physically cross-linking the mucin polymers, whereas the higher molar mass chitosan variants (degree of polymerization of 52 and 100) interact only superficially. The complexation resulted in a tighter mucin polymer mesh that slowed the diffusion of dextran polymers and of the cholera toxin B subunit protein through the mucus gels. These results uncover a new use for low molar mass mucoadhesive polymers such as chitosans as noncytotoxic mucosal barrier enhancers that could be valuable in the prevention and treatment of mucosal diseases.

  • 19.
    Lindh, Jonas
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Carlsson, Daniel O
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Strömme, Maria
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Mihranyan, Albert
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Convenient One-Pot Formation of 2,3-Dialdehyde Cellulose Beads via Periodate Oxidation of Cellulose in Water2014In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 15, no 5, p. 1928-1932Article in journal (Refereed)
  • 20.
    Liu, Jun
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials. Jiangsu Univ, Sch Environm & Safety Engn, Biofuels Inst, Zhenjiang.
    Bacher, Markus
    Univ Nat Resources & Appl Life Sci BOKU, Dept Chem, Vienna.
    Rosenau, Thomas
    Univ Nat Resources & Appl Life Sci BOKU, Dept Chem, Vienna; Åbo Akad Univ, Lab Wood & Paper Chem, Johan Gadolin Proc Chem Ctr, Turku.
    Willfoer, Stefan
    Åbo Akad Univ, Lab Wood & Paper Chem, Johan Gadolin Proc Chem Ctr, Turku.
    Mihranyan, Albert
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Potentially Immunogenic Contaminants in Wood-Based and Bacterial Nanocellulose: Assessment of Endotoxin and (1,3)-β-d-Glucan Levels2018In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 19, no 1, p. 150-157Article in journal (Refereed)
    Abstract [en]

    Knowledge gaps in the biosafety data of the nanocellulose (NC) for biomedical use through various routes of administration call for closer look at health and exposure evaluation. This work evaluated the potentially immunogenic contaminants levels, for example, endotoxin and (1,3)-β-d-glucan, in four representative NCs, that is, wood-based NCs and bacterial cellulose (BC). The hot-water extracts were analyzed with ELISA assays, HPSEC-MALLS, GC, and NMR analysis. Varying levels of endotoxin and (1,3)-β-d-glucan contaminats were found in these widely used NCs. Although the β-(1,3)-d-glucan was not detected from the NMR spectra due to the small extract samples amount (2–7 mg), the anomerics and highly diastereotopic 6-CH2 signals may suggest the presence of β-(1,4)-linkages with β-(1,6) branching in the polysaccharides of NCs’ hot-water extracts, which were otherwise not detectable in the enzymatic assay. In all, the article highlights the importance of monitoring various water-soluble potentially immunogenic contaminants in NC for biomedical use.

  • 21.
    Mansson, Ronja
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Frenning, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Factors Affecting Enzymatic Degradation of Microgel-Bound Peptides2013In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 14, no 7, p. 2317-2325Article in journal (Refereed)
    Abstract [en]

    Proteolytic degradation and release of microgel-bound peptides was investigated for trypsin, poly(acrylic acid-co-acrylamide) microgels (70-90 mu m in diameter), and oppositely charged polylysine, using a method combination of confocal microscopy and micromanipulator-assisted light microscopy. Results show that trypsin-induced release of polylysine increased with increasing trypsin concentration, decreasing microgel charge density and decreasing peptide molecular weight. While the microgel offered good protection against enzymatic degradation at high microgel charge density, it was also observed that the cationic peptide enabled trypsin to bind throughout the peptide-loaded microgels, even when it did not bind to the peptide-void ones. With the exception of highly charged microgels, proteolytic degradation throughout the peptide-loaded microgel resulted in the generation of short and non-adsorbing peptide stretches, giving rise to the concentration and peptide length dependence observed. A simple random scission model was able to qualitatively capture these experimental findings. collectively, the results demonstrate that microgel charge density, peptide molecular weight, and enzyme concentration greatly influence degradation/release of microgel-bound peptides and need to be considered in the use of microgels, e.g., as carriers for protein and peptide drugs.

  • 22.
    Månsson, Ronja
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Bysell, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Hansson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Schmidtchen, Artur
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Effects of Peptide Secondary Structure on the Interaction with Oppositely Charged Microgels2011In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 12, no 2, p. 419-424Article in journal (Refereed)
    Abstract [en]

    The importance of peptide secondary structure on the interaction between antimicrobial peptides and oppositely charged poly(acrylic acid-co-acrylamide) microgels of various charge density was investigated for EFKRIVQRIKDFLRNLV (EFK17). Through D-enantiomer (EFK17-d/a; E(dF)KR(dI)VQR(dI)KD(dF)LRNLV) or tryptophan (EFK17-W/a; EWKRWVQRWKDFLRNLV) substitutions, both conformation-dependent and -independent amphiphilicity of this peptide could be precisely controlled. Peptide secondary structure was investigated by circular dichroism, whereas microgel deswelling and reswelling in response to peptide binding and release were studied by micromanipulator-assisted light and fluorescence microscopy, and peptide uptake in the microgels was determined from solution depletion measurements. Results show that peptide binding to the microgel is highly influenced by peptide secondary structure. EFK17-a, characterized by an idealized helix with all polar/charged amino acids located at one side of the helix, and all nonpolar/hydrophobic residues on the other, displays pronounced alpha-helix induction on peptide binding to the microgels. EFK17-d/a, on the other hand, displays no such amphiphilic helix induction. Mirroring this, EFK17-a displays substantially higher binding to the microgels than EFK17-d/a as well as much larger peptide-induced microgel deswelling. For EFK17-W/a, both conformation-dependent and -independent amphiphilicity effects were demonstrated. Overall, the results show that peptide conformational aspects need to be considered in peptide/microgel interactions, for example, in the design of microgel carrier systems for peptide drugs.

  • 23.
    Nyström, Lina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Al-Rammahi, Noor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Malekkhaiat Häffner, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Strömstedt, Adam A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Farmakognosi.
    Browning, Kathryn L.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Avidin-biotin cross-linked microgel multilayers as carriers for antimicrobial peptides2018In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 19, no 12, p. 4691-4702Article in journal (Refereed)
    Abstract [en]

    Herein, we report on the formation of cross-linked antimicrobial peptide-loaded microgel multilayers. Poly(ethyl acrylate- co-methacrylic acid) microgels were synthesized and functionalized with biotin to enable the formation of microgel multilayers cross-linked with avidin. Microgel functionalization and avidin cross-linking were verified with infrared spectroscopy, dynamic light scattering, and z-potential measurements, while multilayer formation (up to four layers) was studied with null ellipsometry and quartz crystal microbalance with dissipation (QCM-D). Incorporation of the antimicrobial peptide KYE28 (KYEITTIHNLFRKLTHRLFRRNFGYTLR) into the microgel multilayers was achieved either in one shot after multilayer formation or through addition after each microgel layer deposition. The latter was found to strongly promote peptide incorporation. Further, antimicrobial properties of the peptide-loaded microgel multilayers against Escherichia coli were investigated and compared to those of a peptide-loaded microgel monolayer. Results showed a more pronounced suppression in bacterial viability in suspension for the microgel multilayers. Correspondingly, LIVE/DEAD staining showed promoted disruption of adhered bacteria for the KYE28-loaded multilayers. Taken together, cross-linked microgel multilayers thus show promise as high load surface coatings for antimicrobial peptides.

  • 24.
    Nyström, Lina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Nordström, Randi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Bramhill, Jane
    Manchester University.
    Saunders, Brian R
    Manchester University.
    Álvarez-Asencio, Rubén
    KTH.
    Rutland, Mark W
    KTH.
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Factors Affecting Peptide Interactions with Surface-Bound Microgels2016In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 17, no 2, p. 669-678Article in journal (Refereed)
    Abstract [en]

    Effects of electrostatics and peptide size on peptide interactions with surface-bound microgels were investigated with ellipsometry, confocal microscopy, and atomic force microscopy (AFM). Results show that binding of cationic poly-l-lysine (pLys) to anionic, covalently immobilized, poly(ethyl acrylate-co-methacrylic acid) microgels increased with increasing peptide net charge and microgel charge density. Furthermore, peptide release was facilitated by decreasing either microgel or peptide charge density. Analogously, increasing ionic strength facilitated peptide release for short peptides. As a result of peptide binding, the surface-bound microgels displayed pronounced deswelling and increased mechanical rigidity, the latter quantified by quantitative nanomechanical mapping. While short pLys was found to penetrate the entire microgel network and to result in almost complete charge neutralization, larger peptides were partially excluded from the microgel network, forming an outer peptide layer on the microgels. As a result of this difference, microgel flattening was more influenced by the lower Mw peptide than the higher. Peptide-induced deswelling was found to be lower for higher Mw pLys, the latter effect not observed for the corresponding microgels in the dispersed state. While the effects of electrostatics on peptide loading and release were similar to those observed for dispersed microgels, there were thus considerable effects of the underlying surface on peptide-induced microgel deswelling, which need to be considered in the design of surface-bound microgels as carriers of peptide loads, for example, in drug delivery or in functionalized biomaterials.

  • 25.
    Nyström, Lina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Strömstedt, Adam A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Farmakognosi.
    Schmidtchen, Artur
    Lund University, Lund, Sweden; University of Copenhagen, Copenhagen, Denmark.
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. University of Copenhagen, Copenhagen, Denmark.
    Peptide-Loaded Microgels as Antimicrobial and Anti-Inflammatory Surface Coatings2018In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 19, no 8, p. 3456-3466Article in journal (Refereed)
    Abstract [en]

    Here we report on covalently immobilized poly(ethyl acrylate- co-methacrylic acid) microgels loaded with the host defense peptide KYE28 (KYEITTIHNLFRKLTHRLFRRNFGYTLR), which is derived from human heparin cofactor II, as well as its poly(ethylene glycol)-conjugated (PEGylated) version, KYE28PEG. Peptide loading and release, as well as the consequences of these processes on the microgel and peptide properties, were studied by in situ ellipsometry, confocal microscopy, zeta potential measurements, and circular dichroism spectroscopy. The results show that the microgel-peptide interactions are electrostatically dominated, thus promoted at higher microgel charge density, while PEGylation suppresses peptide binding. PEGylation also enhances the α-helix induction observed for KYE28 upon microgel incorporation. Additionally, peptide release is facilitated at physiological salt concentration, particularly so for KYE28PEG, which illustrates the importance of electrostatic interactions. In vitro studies on Escherichia coli show that the microgel-modified surfaces display potent antifouling properties in both the absence and presence of the incorporated peptide. While contact killing dominates at low ionic strength for the peptide-loaded microgels, released peptides also provide antimicrobial activity in bulk at a high ionic strength. Additionally, KYE28- and KYE28PEG-loaded microgels display anti-inflammatory effects on human monocytes. Taken together, these results not only show that surface-bound microgels offer an interesting approach for local drug delivery of host defense peptides but also illustrate the need to achieve high surface loads of peptides for efficient biological effects.

  • 26.
    Ossipov, Dmitri A.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Materials Chemistry, Polymer Chemistry.
    Piskounova, Sonya
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Materials Chemistry, Polymer Chemistry.
    Varghese, Oommen P.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Materials Chemistry, Polymer Chemistry.
    Hilborn, Jöns
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Materials Chemistry, Polymer Chemistry.
    Functionalization of Hyaluronic Acid with Chemoselective Groups via a Disulfide-Based Protection Strategy for In Situ Formation of Mechanically Stable Hydrogels2010In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 11, no 9, p. 2247-2254Article in journal (Refereed)
    Abstract [en]

    Functionalization of hyaluronic acid (HA) with chemoselective groups enables in situ (in vivo) formation of HA-based materials in minimally invasive injectable manner. Current methods of HA modification with such groups primarily rely on the use of a large excess of a reagent to introduce a unique reactive handle into HA and, therefore, are difficult to control. We have developed the new protective group strategy based on initial mild cleavage of a disulfide bond followed by elimination of the generated 2-thioethoxycarbonyl moiety ultimately affording free amine-type functionality, such as hydrazide, aminooxy, and carbazate. Specifically, new modifying homobifunctional reagents have been synthesized that contain a new divalent disulfide-based protecting group. Amidation of HA with these reagents gives rise to either one-end coupling product or to intra/intermolecular cross-linking of the HA chains. However, after subsequent treatment of the amidation reaction mixture with dithiothreitol (DTT), these cross-linkages are cleaved, ultimately exposing free amine-type groups. The same methodology was applied to graft serine residues to the HA backbone, which were subsequently oxidized into aldehyde groups. The strategy therefore encompasses a new approach for mild and highly controlled functionalization of HA with both nucleophilic and electrophilic chemoselective functionalities with the emphasis for the subsequent conjugation and in situ cross-linking. A series of new hydrogel materials were prepared by mixing the new HA-aldehyde derivative with different HA-nucleophile counterparts. Rheological properties of the formed hydrogels were determined and related to the structural characteristics of the gel networks. Human dermal fibroblasts remained viable while cultured with the hydrogels for 3 days, with no sign of cytotoxicity, suggesting that the gels described in this study are candidates for use as growth factors delivery vehicles for tissue engineering applications.

  • 27.
    Paidikondala, Maruthibabu
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Nawale, Ganesh N.
    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.
    Insights into siRNA Transfection in Suspension: Efficient Gene Silencing in Human Mesenchymal Stem Cells Encapsulated in Hyaluronic Acid Hydrogel2019In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 20, no 3, p. 1317-1324Article in journal (Refereed)
    Abstract [en]

    Small interfering RNAs (siRNAs) are powerful toolsfor post-transcriptional gene silencing, which offers enormousopportunities for tissue engineering applications. However, poorserum stability, inefficient intracellular delivery, and inevitabletoxicity of transfection reagents are the key barriers for their clinicaltranslation. Thus, innovative strategies that allow safe and efficientintracellular delivery of the nucleic acid drugs at the desired site isurgently needed for a smooth clinical translation of therapeuticallyappealing siRNA-based technology. In this regard, we havedeveloped an innovative siRNA transfection protocol that employsa short incubation time of just 5 min. This allows easy transfection insuspension followed by transplantation of the cells in a hyaluronicacid (HA) hydrogel system. We also report here the unique ability ofsiRNA to bind HA that was quantified by siRNA release andrheological characterization of the HA-hydrogel. Such interactions also showed promising results to deliver functional siRNA insuspension transfection conditions within 30 min using native HA, although removal of excess HA by centrifugation seem to beessential. In the 2D experiments, suspension transfection of hMSCs with RNAiMAX resulted in ≈90% gene silencing (with orwithout removal of the excess reagent by centrifugation), while HA demonstrated a modest ≈40% gene silencing after removalof excess reagent after 30 min. Transplantation of such transfected cells in the HA-hydrogel system demonstrated an improvedknockdown (≈90% and ≈60% with RNAiMAX and HA respectively after 48 h), with lower cytotoxicity (up to 5-days) asdetermined by PrestoBlue assay. The gene silencing efficiency in the 2D and 3D conditions were also confirmed at the proteinlevels by Western blot analysis. We postulate this novel transfection method could be applied for in vivo applications as it allowsminimal manipulation of cells that are to be transplanted and reduce toxicity.

  • 28.
    Ranga, Adrian
    et al.
    Ecole Polytech Fed Lausanne, Sch Life Sci, Inst Bioengn, Lab Stem Cell Bioengn, CH-1015 Lausanne, Switzerland.;Ecole Polytech Fed Lausanne, Sch Engn, CH-1015 Lausanne, Switzerland.;Katholieke Univ Leuven, Dept Mech Engn, Biomech Sect, Celestijnenlaan 300, B-3001 Leuven, Belgium..
    Lutolf, Matthias P.
    Ecole Polytech Fed Lausanne, Sch Life Sci, Inst Bioengn, Lab Stem Cell Bioengn, CH-1015 Lausanne, Switzerland.;Ecole Polytech Fed Lausanne, Sch Engn, CH-1015 Lausanne, Switzerland.;Ecole Polytech Fed Lausanne, Sch Basic Sci, Inst Chem Sci & Engn, CH-1015 Lausanne, Switzerland..
    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.
    Hyaluronic Acid Hydrogels Formed in Situ by Transglutaminase-Catalyzed Reaction2016In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 17, no 5, p. 1553-1560Article in journal (Refereed)
    Abstract [en]

    Enzymatically cross-linked hydrogels can be formed in situ and permit highly versatile and selective tethering of bioactive molecules, thereby allowing for a wealth of applications in cell biology and tissue engineering. While a number of studies have reported the bioconjugation of extracellular matrix (ECM) proteins and peptides into such matrices, the site specific incorporation of biologically highly relevant polysaccharides such as hyaluronic acid (HA) has thus far not been reported, limiting our ability to reconstruct this key feature of the in vivo ECM. Here we demonstrate a novel strategy for transglutaminase-mediated covalent linking of HA moieties to a synthetic poly(ethylene glycol) (PEG) macromer resulting in the formation of hybrid HA-PEG hydrogels. We characterize the ensuing matrix properties and demonstrate how these cytocompatible gels can serve to modulate the cellular phenotype of human mammary cancer epithelial cells as well as mouse myoblasts. The use of HA as a novel building block in the increasingly varied library of synthetic PEG-based artificial ECMs should have applications as a structural as well as a signaling component and offers significant potential as an injectable matrix for regenerative medicine.

  • 29.
    Singh, Shalini
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Kalle, Martina
    Papareddy, Praveen
    Schmidtchen, Artur
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lipopolysaccharide Interactions of C-Terminal Peptides from Human Thrombin2013In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 14, no 5, p. 1482-1492Article in journal (Refereed)
    Abstract [en]

    Interactions with bacterial lipopolysaccharide (LPS), both in aqueous solution and in lipid membranes, were investigated for a series of amphiphilic peptides derived from the C-terminal region of human thrombin, using ellipsometry, dual polarization interferometry, fluorescence spectroscopy, circular dichroism (CD), dynamic light scattering, and z-potential measurements. The ability of these peptides to block endotoxic effects caused by LPS, monitored through NO production in macrophages, was compared to peptide binding to LPS and its endotoxic component lipid A, and to size, charge, and secondary structure of peptide/LPS complexes. While the antiendotoxic peptide GKY25 (GKYGFYTHVFRL-KKWIQKVIDQFGE) displayed significant binding to both LPS and lipid A, so did two control peptides with either selected D-amino acid substitutions or with maintained composition but scrambled sequence, both displaying strongly attenuated antiendotoxic effects. Hence, the extent of LPS or lipid A binding is not the sole discriminant for the antiendotoxic effect of these peptides. In contrast, helix formation in peptide/LPS complexes correlates to the antiendotoxic effect of these peptides and is potentially linked to this functionality. Preferential binding to LPS over lipid membrane was furthermore demonstrated for these peptides and preferential binding to the lipid A moiety within LPS inferred.

  • 30.
    Singh, Shalini
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Papareddy, Praveen
    Morgelin, Matthias
    Schmidtchen, Artur
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Effects of PEGylation on Membrane and Lipopolysaccharide Interactions of Host Defense Peptides2014In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 15, no 4, p. 1337-1345Article in journal (Refereed)
    Abstract [en]

    Effects of poly(ethylene glycol) (PEG) conjugation on peptide interactions with lipid membranes and lipopolysaccharide (LPS) were investigated for KYE28 (KYEITTIHNLFRKLTHRLFRRNFGYTLR), an antimicrobial and anti-inflammatory peptide derived from human heparin cofactor II. In particular, effects of PEG length and localization was investigated by ellipsometry, circular dichroism, nanoparticle tracking analysis, and fluorescence/electron microscopy. PEGylation of KYE28 reduces peptide binding to lipid membranes, an effect accentuated at increasing PEG length, but less sensitive to conjugation site. The reduced binding causes suppressed liposome leakage induction, as well as bacterial lysis. As a result of this, the antimicrobial effects of KYE28 is partially lost with increasing PEG length, but hemolysis also strongly suppressed and selecticity improved. Through this, conditions can be found, at which the PEGylated peptide displays simultaneously efficient antimicrobial affects and low hemolysis in blood. Importantly, PEGylation does not markedly affect the anti-inflammatory effects of KYE28. The combination of reduced toxicity, increased selectivity, and retained anti-inflammatory effect after PEGylation, as well as reduced scavenging by serum proteins, thus shows that PEG conjugation may offer opportunities in the development of effective and selective anti-inflammatory peptides.

  • 31. Veiseh, Mandana
    et al.
    Breadner, Daniel
    Ma, Jenny
    Akentieva, Natalia
    Savani, Rashmin C.
    Harrison, Rene
    Mikilus, David
    Collis, Lisa
    Gustafson, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical and Physiological Chemistry.
    Lee, Ting-Yim
    Koropatnick, James
    Luyt, Leonard G.
    Bissell, Mina J.
    Turley, Eva A.
    Imaging of Homeostatic, Neoplastic, and Injured Tissues by HA-Based Probes2012In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 13, no 1, p. 12-22Article in journal (Refereed)
    Abstract [en]

    An increase in hyaluronan (HA) synthesis, cellular uptake, and metabolism occurs during the remodeling of tissue microenvironments following injury and during disease processes such as cancer. We hypothesized that multimodality HA-based probes selectively target and detectably accumulate at sites of high HA metabolism, thus providing a flexible imaging strategy for monitoring disease and repair processes. Kinetic analyses confirmed favorable available serum levels of the probe following intravenous (i.v.) or subcutaneous (s.c.) injection. Nuclear (technetium-HA, Tc-99m-HA, and iodine-HA, I-125-HA), optical (fluorescent Texas Red-HA, TR-HA), and magnetic resonance (gadolinium-HA, Gd-HA) probes imaged liver (Tc-99m-HA), breast cancer. cells/xenografts (TR-HA, Gd-HA), and vascular injury (I-125-HA, TR-HA). Targeting of HA probes to these sites. appeared to result from selective HA receptor-dependent localization. Our results suggest that HA-based probes, which do not require, polysaccharide backbone modification to achieve favorable half-life and distribution, can detect elevated HA metabolism in homeostatic, injured, and diseased tissues.

  • 32.
    Wang, Shujiang
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Oommen, Oommen P.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Yan, Hongji
    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.
    Mild and Efficient Strategy for Site-Selective Aldehyde Modification of Glycosaminoglycans: Tailoring Hydrogels with Tunable Release of Growth Factor2013In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 14, no 7, p. 2427-2432Article in journal (Refereed)
    Abstract [en]

    Aldehydes have been used as an important bioorthogonal chemical reporter for conjugation of large polymers and bioactive substances. However, generating aldehyde functionality on carbohydrate-based biopolymers without changing its native chemical structure has always persisted as a challenging task. The common methods employed to achieve this require harsh reaction conditions, which often compromise the structural integrity and biological function of these sensitive molecules. Here we report a mild and simple method to graft aldehydes groups on glycosaminoglycans (GAGs) in a site-selective manner without compromising the structural integrity of the biopolymer. This regio-selective modification was achieved by conjugating the amino-glycerol moiety on the carboxylate residue of the polymer, which allowed selective cleavage of pendent diol groups without interfering with the C2C3 diol groups of the native glucopyranose residue. Kinetic evaluation of this reaction demonstrated significant differences in second-order reaction rate for periodate oxidation (by four-orders of magnitude) between the two types of vicinal diols. We employed this chemistry to develop aldehyde modifications of sulfated and nonsulfated GAGs such as hyaluronic acid (HA), heparin (HP), and chondroitin sulfate (CS). We further utilized these aldehyde grafted GAGs to tailor extracellular matrix mimetic injectable hydrogels and evaluated its rheological properties. The composition of the hydrogels was also found to modulate release of therapeutic protein such as FGF-2, demonstrating controlled release (60%) for over 14 days. In short, our result clearly demonstrates a versatile strategy to graft aldehyde groups on sensitive biopolymers under mild conditions that could be applied for various bioconjugation and biomedical applications such as drug delivery and regenerative medicine.

  • 33.
    Widenbring, Ronja
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Frenning, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Chain and Pore-Blocking Effects on Matrix Degradation in Protein-Loaded Microgels2014In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 15, no 10, p. 3671-3678Article in journal (Refereed)
    Abstract [en]

    Factors affecting matrix degradation in protein-loaded microgels were investigated for dextran-based microgels, the sugar-binding protein Concanavalin A (ConA), and the dextran-degrading enzyme Dextranase. For this system, effects of enzyme, protein, and glucose concentrations, as well as pH, were considered. Microgel network degradation was monitored by micromanipulator-assisted light microscopy, whereas enzyme and protein distributions were monitored by confocal microscopy. Results show that Dextranase-mediated microgel degradation increased with increasing enzyme concentration, whereas an increased ConA loading in the dextran microgels caused a concentration-dependent decrease in microgel degradation. In the presence of glucose, competitive release of microgel-bound ConA restored the microgel degradation observed in the absence of ConA. To clarify effects of mass transport limitations, microgel degradation was compared to that of non-cross-linked dextran, demonstrating that ConA limits enzyme substrate access in dextran microgels primarily through pore blocking and induction of pore shrinkage. The experimentally observed effects were qualitatively captured by a modified Michaelis-Menten approach for spherical symmetry, in which network blocking by ConA was included. Taken together, the results demonstrate that matrix degradation of protein-loaded microgels depends sensitively on a number of factors, which need to be considered in the use of microgels in biomedical applications.

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