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Direct ”Click” Synthesis of Hybrid Bisphosphonate-Hyaluronic Acid Hydrogel in Aqueous Solution for Biomineralization
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences. (Electron Microscopy and Nanoengineering)
Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences. (Electron Microscopy and Nanoengineering)
Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences. (Electron Microscopy and Nanoengineering)
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2012 (English)In: Chemistry of Materials, ISSN 0897-4756, E-ISSN 1520-5002, Vol. 24, no 9, 1690-1697 p.Article in journal (Refereed) Published
Abstract [en]

We report the synthesis of injectable in situ forming hybrid hydrogel material and investigate its ability to support the mineralization process under mild conditions. To achieve this, we have prepared a hyaluronic acid (HA) derivative that is dually functionalized with cross-linkable hydrazide groups and bisphosphonate ligands (HA-hy-BP). The hybrid hydrogel can be formed by simple mixing of two solutions: the solution of HA-hy-BP and the Ca2+ ions containing solution of aldehyde-derivatized HA (HA-al). We found that the conjugation of BP, a P-C-P analogue of pyrophosphate, to the hydrogel matrix promotes an efficient and fast mineralization of the matrix. The mineralization is facilitated by the strong interaction between BP residues and Ca2+ ions that serve as nanometer-sized nucleation points for further calcium phosphate deposition within the HA hydrogel. Compared with previously reported hydrogel template-driven mineralization techniques, the present approach is maximally adapted for clinical settings since the formation of the hybrid takes place during quick mixing of the sterilized solutions. Moreover, the hybrid hydrogel is formed from in vivo degradable components of the extracellular matrix and therefore can be remodeled in vivo through concerted HA degradation and calcium phosphate mineralization.

Place, publisher, year, edition, pages
2012. Vol. 24, no 9, 1690-1697 p.
Keyword [en]
hybrid organic-inorganic materials, injectable materials, hydrogels, hyaluronic acid, mineralization
National Category
Biochemistry and Molecular Biology Materials Engineering Polymer Chemistry
Research subject
Engineering Science with specialization in Materials Science; Chemistry with specialization in Polymer Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-171989DOI: 10.1021/cm300298nISI: 000303628100019OAI: oai:DiVA.org:uu-171989DiVA: diva2:513190
Available from: 2012-03-30 Created: 2012-03-30 Last updated: 2017-12-07Bibliographically approved
In thesis
1. Transmission Electron Microscopy of Graphene and Hydrated Biomaterial Nanostructures: Novel Techniques and Analysis
Open this publication in new window or tab >>Transmission Electron Microscopy of Graphene and Hydrated Biomaterial Nanostructures: Novel Techniques and Analysis
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Transmission Electron Microscopy (TEM) on light element materials and soft matters is problematic due to electron irradiation damage and low contrast. In this doctoral thesis techniques were developed to address some of those issues and successfully characterize these materials at high resolution. These techniques were demonstrated on graphene flakes, DNA/magnetic beads and a number of water containing biomaterials. The details of these studies are given below.

A TEM based method was presented for thickness characterization of graphene flakes. For the thickness characterization, the dynamical theory of electron diffraction is used to obtain an analytical expression for the intensity of the transmitted electron beam as a function of thickness. From JEMS simulations (experiments) the absorption constant λ in a low symmetry orientation was found to be ~ 208 nm (225 ± 9 nm). When compared to standard techniques for thickness determination of graphene/graphite, the method has the advantage of being relatively simple, fast and requiring only the acquisition of bright-field (BF) images. Using the proposed method, it is possible to measure the thickness change due to one monolayer of graphene if the flake has uniform thickness over a larger area.

A real-space TEM study on magnetic bead-DNA coil interaction was conducted and a statistical analysis of the number of beads attached to the DNA-coils was performed. The average number of beads per DNA coil was calculated around 6 and slightly above 2 for samples with 40 nm and 130 nm beads, respectively. These results are in good agreement with magnetic measurements. In addition, the TEM analysis supported an earlier hypothesis that 40 nm beads are preferably attached interior of the DNA-coils while 130 nm beads closer to the exterior of the coils.

A focused ion-beam in-situ lift-out technique for hydrated biological specimens was developed for cryo-TEM. The technique was demonstrated on frozen Aspergillus niger spores which were frozen with liquid nitrogen to preserve their cellular structures. A thin lamella was prepared, lifted out and welded to a TEM grid. Once the lamella was thinned to electron transparency, the grid was cryogenically transferred to the TEM using a cryo-transfer bath. The structure of the cells was revealed by BF imaging. Also, a series of energy filtered images was acquired and C, N and Mn elemental maps were produced. Furthermore, 3 Å lattice fringes of the underlying Al support were successfully resolved by high resolution imaging, confirming that the technique has the potential to extract structural information down to the atomic scale. The experimental protocol is ready now to be employed on a large variety of samples e.g. soft/hard matter interfaces.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. 124 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 917
Keyword
Graphene flakes, magnetic beads/DNA coils, hydrated biomaterials, transmission electron microscopy, focused ion beam/scanning electron microscopy, bright-field/dark-field imaging, high resolution imaging, electron diffraction and cryogenic temperatures
National Category
Engineering and Technology
Research subject
Materials Science
Identifiers
urn:nbn:se:uu:diva-171991 (URN)978-91-554-8333-3 (ISBN)
Public defence
2012-05-21, Häggsalen, Ångströmlaboratoriet, Lägerhyddsvägen 1, Uppsala, 10:15 (English)
Opponent
Supervisors
Available from: 2012-04-26 Created: 2012-03-30 Last updated: 2012-08-01Bibliographically approved
2. Multi-functional Hyaluronan Based Biomaterials for Biomedical Applications
Open this publication in new window or tab >>Multi-functional Hyaluronan Based Biomaterials for Biomedical Applications
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis presents strategies for constructing multi-functional biomaterials based on hyaluronan (HA) derivatives for various biomedical applications, such as drug delivery, tissue regeneration, and imaging biomaterials. The aim of this study is to improve the functionalities of HA biomaterials as well as simplify the preparation procedures.  Native HA polymer contains D-glucuronic acid residue with a carboxyl group per disaccharide unit that can be easily modified by carbodiimide-mediated amidation reaction. Therefore, we have designed a series of orthogonal groups (hydrazide, carbazate, aldehyde, and thiol) that can be linked to HA under mild conditions using the carbodiimide chemistry. Multiple functionalities can be introduced to the obtained HA derivatives via chemoselective “click”-type transformations.  

The modified HA derivatives were used for the preparation of either nanogel particles (NPs) or bulk hydrogels. Due to “click” character of the reactions used, structural HA transformations were performed with high fidelity on different scales including molecular (polymers), nanometer (NPs), and a visible scale (bulk hydrogels). By linking pyrene or camptothecin to hydrophilic HA backbone, amphiphilic polymers were obtained and utilized as drug delivery carriers or prodrugs, respectively. Subsequently, physically loaded drug (doxorubicin) could be released upon degradation of HA carriers, while the chemically linked camptothecin was released intact by a thiol-triggered cleavage reaction. Bisphosphonated HA (HA-BP) polymers were prepared to induce hydrogel scaffold bio-mineralization for bone regeneration application. Moreover, we could recruit strong binding capacity of bisphosphonate (BP) groups to calcium ions for the formation of physically crosslinked HA-BP gel upon simple mixing of the polymer and calcium phosphate nanoparticle components. This gel was more stable in vivo compared to hydrazone crosslinked HA gels. Furthermore, the hydrogel composed of fluorine-19 (19F) linked HA polymer was successfully observed by both 1H and 19F MR imaging.        

In conclusion, the presented herein study describes new approaches for building up multi-functional biomaterials from the HA-based blocks. The utilization of carbodiimide and click chemistries along with the enzymatic degradation of HA allowed simple and efficient interconversion between HA macromolecules, nanoparticles and macroscopic hydrogels. These HA-based biomaterials show high potential for use in the fields of drug delivery, bone regeneration, and imaging techniques.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2014. 51 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1155
Keyword
hyaluronan, biomaterials functionalizations, biomedical applications, orthogonal chemistry, drug delivery, tissue regeneration, MRI
National Category
Polymer Chemistry Materials Chemistry
Research subject
Chemistry with specialization in Polymer Chemistry
Identifiers
urn:nbn:se:uu:diva-224371 (URN)978-91-554-8974-8 (ISBN)
Public defence
2014-09-17, Häggsalen, Ångströmlaboratoriet, Lägerhyddsvägen 1, Uppsala, 09:00 (English)
Opponent
Supervisors
Available from: 2014-06-04 Created: 2014-05-09 Last updated: 2014-06-30

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Yang, XiaAkhtar, SultanRubino, StefanoLeifer, KlausHilborn, JönsOssipov, Dmitri

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