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First Aldol-Crosslinked Hyaluronic Acid Hydrogel: Fast and Hydrolytically Stable Gel with Tissue Adhesive Properties
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
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 Mechanics.ORCID iD: 0000-0002-0491-1077
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
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(English)In: Chemical Sciences Journal, ISSN 2150-3494Article in journal (Refereed) Submitted
Abstract [en]

Currently, there are limited approaches to tailor 3D scaffolds crosslinked with a stable covalent C-C bond that does not require any catalysts or initiators. We present here the first hydrogels employing aldol condensation chemistry that exhibit exceptional physicochemical properties. We investigated the aldol-crosslinking chemistry using two types of aldehyde-modified hyaluronic acid (HA) derivatives, namely; an enolizable HA-aldehyde (HA-Eal) and a non-enolizable HA-aldehyde (HA-Nal). Hydrogels formed using HA-Eal demonstrate inferior crosslinking efficiency (due to intramolecular loop formation), when compared with hydrogels formed by mixing HA-Eal and HA-NaI leading to a cross-aldol product. The change in mechanical properties as a result of crosslinking at different pH is determined using rheological measurements and is interpreted in terms of molecular weight between cross-links (Mc). The novel HA cross-aldol hydrogels demonstrate excellent hydrolytic stability and favorable mechanical properties but allow hyaluronidase mediated enzymatic degradation. Interestingly, residual aldehyde functionality within the aldol product leads to adhesion to tissue as demonstrated by bonding two bone tissues. The aldehyde functionality also permits facile post-synthetic modifications with nucleophilic reagents such as Alexa FluorTM 488. Finally, we demonstrate that the novel hydrogel is biocompatible with encapsulated stem cells that show a linear rate of expansion in our 3–6 days of study.

Keywords [en]
hyaluronic acid, aldol chemisty, stable hydrogels, tissue adhesive
National Category
Materials Chemistry
Research subject
Chemistry with specialization in Materials Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-374999OAI: oai:DiVA.org:uu-374999DiVA, id: diva2:1282438
Available from: 2019-01-24 Created: 2019-01-24 Last updated: 2019-01-24
In thesis
1. Insights into Covalent Chemistry for the Developmen­t of Biomaterials
Open this publication in new window or tab >>Insights into Covalent Chemistry for the Developmen­t of Biomaterials
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Covalent cross-linking chemistry is currently exploited in the preparation of biomaterial for biomedical applications. Choice of these chemistries for the preparation of biomaterials and bioconjugates strongly influences the biological output of these materials. Therefore, this thesis aims to develop novel bioconjugation strategies understanding their advantages and drawbacks. Our results provide new insight to adapt these chemical transformations for a specific application.

The first part of this thesis points out the relevance of tuning different properties of biomaterials with specific emphasis on the development of hyaluronic acid (HA) hydrogels. The second part of the thesis describes how different chemical transformations including hydrazone formation (Paper I), thiazolidine formation (Paper II), cross-aldol addition reaction (Paper III) and disulfide formation (Paper IV) dictate material properties.

This thesis explores both basic organic reaction mechanism and application of these reactions to influence material characteristics. The detailed study of the reaction conditions, kinetics, and stability of the products will help to understand the mechanical properties, hydrolytic stability, and degradability of the materials described here.

Additionally, we performed degradation studies of gadolinium labeled HA hydrogels using magnetic resonance imaging. Furthermore, we also explored post-synthetic modification of hydrogels to link model fluorescent moieties as well as explored the tissue adhesive properties using Schiff-base formation.

In summary, this thesis presents a selection of different covalent chemistries for the design of advanced biomaterials. The advantages and disadvantages of these chemistries are rigorously investigated. We believe, such an investigation provides a better understanding of the bioconjugation strategies for the preparation of biomaterials with potential clinical translation.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2019. p. 64
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1768
Keywords
hyaluronic acid, hydrogel, biomaterials, covalent chemistry, biomedical applications, MRI
National Category
Materials Chemistry Polymer Chemistry Organic Chemistry
Research subject
Chemistry with specialization in Materials Chemistry; Chemistry with specialization in Polymer Chemistry
Identifiers
urn:nbn:se:uu:diva-375002 (URN)978-91-513-0564-6 (ISBN)
Public defence
2019-03-14, Häggsalen, 10132, Ångströmlaboratoriet, Lägerhyddsvägen 1, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2019-02-21 Created: 2019-01-24 Last updated: 2019-02-21

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Bermejo, DanielKadekar, SandeepTavares da Costa, Marcus ViniciusPodiyan, OommenGamstedt, E. KristoferHilborn, JönsVarghese, Oommen P.

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Bermejo, DanielKadekar, SandeepTavares da Costa, Marcus ViniciusPodiyan, OommenGamstedt, E. KristoferHilborn, JönsVarghese, Oommen P.
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