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Multi-functional Hyaluronan Based Biomaterials for Biomedical Applications
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
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 [en]
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: urn:nbn:se:uu:diva-224371ISBN: 978-91-554-8974-8 (print)OAI: oai:DiVA.org:uu-224371DiVA: diva2:716486
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
List of papers
1. Modular approach to functional hyaluronic acid hydrogels using orthogonal chemical reactions
Open this publication in new window or tab >>Modular approach to functional hyaluronic acid hydrogels using orthogonal chemical reactions
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2010 (English)In: Chemical Communications, ISSN 1359-7345, E-ISSN 1364-548X, Vol. 46, no 44, 8368-8370 p.Article in journal (Refereed) Published
Abstract [en]

A modular approach for the synthesis of hyaluronic acid hydrogels using orthogonal chemoselective reactions for subsequent enzymatic decomposition to nanoparticles is described.

National Category
Polymer Chemistry
Research subject
Chemistry with specialization in Polymer Chemistry
Identifiers
urn:nbn:se:uu:diva-135363 (URN)10.1039/c0cc03055d (DOI)000283690400014 ()
Available from: 2010-12-07 Created: 2010-12-06 Last updated: 2017-12-11Bibliographically approved
2. Preparation of hyaluronic acid nanoparticles via hydrophobic association assisted chemical cross-linking: an orthogonal modular approach
Open this publication in new window or tab >>Preparation of hyaluronic acid nanoparticles via hydrophobic association assisted chemical cross-linking: an orthogonal modular approach
2011 (English)In: Soft Matter, ISSN 1744-683X, E-ISSN 1744-6848, Vol. 7, no 16, 7517-7525 p.Article in journal (Refereed) Published
Abstract [en]

The objective of this study was to develop an efficient and stable drug delivery nanocarrier based on a dually functionalized hyaluronic acid (HA) derivative which could be used as a long circulating drug delivery vehicle. Self-assembled HA nanoparticles (HA NPs) were prepared by attaching pyrene to the HA backbone and the obtained physical NPs were stabilized by chemical cross-linking of the HA chains to form hydrophobic core-hydrophilic shell NPs. Orthogonal chemoselective reactions were applied for conversion of HA into its amphiphilic derivative and subsequent cross-linking of the formed micellar-type associates. Chemical stabilization of the physical HA associates afforded therefore very stable nanoparticles that could easily be re-suspended in aqueous media after freeze-drying. In contrast, freeze-drying of the uncross-linked physically associated particles resulted in a non-soluble material. Doxorubicin (DOX), a typical anticancer drug, was entrapped into HA NPs via ionic and/or hydrophobic interactions and used for in vitro drug release. Higher loading efficiency and the slower release profile of DOX from HA NPs were obtained with the hydrophobically encapsulated drug. We have shown that free HA NPs were readily taken up by NIH 3T3 cells without causing any toxicity to the cells, while the DOX-loaded HA NPs resulted in increased cell death comparable to the free drug. This study clearly showed the applicability of orthogonal chemoselective modifications for the synthesis of stable HA nanogel particles as a potential cancer-targeted drug delivery system.

National Category
Natural Sciences Polymer Chemistry
Research subject
Chemistry with specialization in Polymer Chemistry
Identifiers
urn:nbn:se:uu:diva-158426 (URN)10.1039/c1sm05785e (DOI)000293412900049 ()
Available from: 2011-09-08 Created: 2011-09-07 Last updated: 2017-12-08Bibliographically approved
3. A hyaluronic acid-camptothecin nanoprodrug with cytosolic mode of activation for targeting cancer
Open this publication in new window or tab >>A hyaluronic acid-camptothecin nanoprodrug with cytosolic mode of activation for targeting cancer
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2013 (English)In: POLYM CHEM-UK, ISSN 1759-9954, Vol. 4, no 17, 4621-4630 p.Article in journal (Refereed) Published
Abstract [en]

We have developed a nanoprodrug that enables the uptake by cancer cells and the subsequent intracellular activation. The nanoprodrug is composed of a cancer cell-targeting biopolymer, hyaluronic acid (HA), and an anti-cancer drug, camptothecin (CPT). The chemical linkage between the polymer and the drug is stable outside the cells, thus maintaining the drug in an "off" state. The specific uptake of the nanoprodrug by cancer cells should then lead to an environmental change that results in the cleavage of the linkage, liberating the drug and thus entering the "on" state. The natural cancer-targeting biopolymer HA was modified with aldehyde "click" groups. This "clickable" HA was then conjugated to CPT modified with a hydrazide linker using a mild hydrazone-coupling reaction. The linker consists of a thiol-activated self-immolative dithioethoxycarbonyl spacer, which is stable in PBS buffer but should be rapidly cleaved in the reductive cytosolic environment of cancer cells. The resulting HA-CPT nanoprodrug released CPT only at low levels in PBS buffer. However, the drug was efficiently cleaved after the addition of dithiothreitol (DTT). Consistent with these data, the HA-CPT nanoprodrug showed a 3-fold greater cytotoxicity to cancer cells compared to free CPT. Fluorescence microscopy confirmed the rapid and efficient uptake of the HA-CPT nanoprodrug by the cancer cells.

National Category
Natural Sciences
Identifiers
urn:nbn:se:uu:diva-207489 (URN)10.1039/c3py00402c (DOI)000323361300013 ()
Available from: 2013-09-17 Created: 2013-09-16 Last updated: 2014-06-30Bibliographically approved
4. Direct ”Click” Synthesis of Hybrid Bisphosphonate-Hyaluronic Acid Hydrogel in Aqueous Solution for Biomineralization
Open this publication in new window or tab >>Direct ”Click” Synthesis of Hybrid Bisphosphonate-Hyaluronic Acid Hydrogel in Aqueous Solution for Biomineralization
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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.

Keyword
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:nbn:se:uu:diva-171989 (URN)10.1021/cm300298n (DOI)000303628100019 ()
Available from: 2012-03-30 Created: 2012-03-30 Last updated: 2017-12-07Bibliographically approved
5. Self-healing Hybrid Nanocomposites consisting of Bisphosphonated Hyaluronan and Calcium Phosphate Nanoparticles
Open this publication in new window or tab >>Self-healing Hybrid Nanocomposites consisting of Bisphosphonated Hyaluronan and Calcium Phosphate Nanoparticles
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2014 (English)In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 35, no 25, 6918-6929 p.Article in journal (Refereed) Published
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.

National Category
Materials Chemistry Polymer Chemistry
Identifiers
urn:nbn:se:uu:diva-224369 (URN)10.1016/j.biomaterials.2014.05.003 (DOI)000338386800024 ()
Available from: 2014-05-09 Created: 2014-05-09 Last updated: 2017-12-05Bibliographically approved
6. Injectable hyaluronic acid hydrogel for F-19 magnetic resonance imaging
Open this publication in new window or tab >>Injectable hyaluronic acid hydrogel for F-19 magnetic resonance imaging
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2014 (English)In: Carbohydrate Polymers, ISSN 0144-8617, E-ISSN 1879-1344, Vol. 110, 95-99 p.Article in journal (Refereed) Published
Abstract [en]

We report on a19F labeled injectable hyaluronic acid (HA) hydrogel that can be monitored by both 1H and 19F MR imaging. The HA based hydrogel formed via carbazone reaction can be obtained within a minute by simple mixing of HA-carbazate and HA-aldehyde derivatized polymers. 19F contrast agent was linked to with carbazate and thiol dually functionalized HA via orthogonal Michael addition reaction which afforded cross-linkable and 19F labeled HA. The 19F labeling of HA polymer did not affect the mechanical properties of the formed hydrogel. As a result, the shape of a hydrogel sample could be imaged very well by both 1H MRI and high resolution19F MRI. This hydrogel has high potential in clinical applications since it is injectable, biocompatible, and can be tracked in a minimally invasive manner. The present approach can be applied in preparation of injectable 19F labeled hydrogel biomaterials from other natural biomacromolecules.

National Category
Polymer Chemistry Materials Chemistry
Identifiers
urn:nbn:se:uu:diva-224259 (URN)10.1016/j.carbpol.2014.03.070 (DOI)000338005000013 ()
Note

Injectable hyaluronic acid hydrogel for 19F magnetic resonance imaging

Available from: 2014-05-09 Created: 2014-05-07 Last updated: 2017-12-05Bibliographically approved

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