DOI: 10.1002/chem.201603748
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Hydrogels |Hot Paper|
A Synthetic Toolbox for the In Situ Formation of Functionalized
Homo- and Heteropolysaccharide-Based Hydrogel Libraries
Nick Dibbert,[a] Andreas Krause,[a] Julio-Cesar Rios-Camacho,[b] Ina Gruh,[b]
Andreas Kirschning,*[a] and Gerald Drꢀger*[a]
Dedicated to Professor Gerhard Bringmann on the occasion of his 65th birthday
Abstract: A synthetic toolbox for the introduction of aldehy-
do and hydrazido groups into the polysaccharides hyaluron-
ic acid, alginate, dextran, pullulan, glycogen, and carboxy-
methyl cellulose and their use for hydrogel formation is re-
ported. Upon mixing differently functionalized polysaccha-
rides derived from the same natural precursor, hydrazone
cross-linking takes place, which results in formation of a hy-
drogel composed of one type of polysaccharide backbone.
Likewise, hydrogels based on two different polysaccharide
strands can be formed after mixing the corresponding alde-
hydo- and hydrazido-modified polysaccharides. A second
line of these studies paves the way to introduce a biomedi-
cally relevant ligand, namely, the adhesion factor cyclic RGD
pentapeptide, by using an orthogonal click reaction. This set
of modified polysaccharides served to create a library of hy-
drogels that differ in the combination of polysaccharide
strands and the degree of cross-linking. The different hydro-
gels were evaluated with respect to their rheological proper-
ties, their ability to absorb water, and their cytotoxicity to-
wards human fibroblast cell cultures. None of the hydrogels
studied were cytotoxic, and, hence, they are in principal bio-
compatible for applications in tissue engineering.
Introduction
tion protocol, one is able to extend the biological or physico-
chemical properties of such biomaterials. Particularly interest-
ing derivatizations are fluorescent labels, adhesion factors and
drugs, for example, with antibacterial or inhibitory properties
against biofilms.[20] As a result, bioconjugates are created that
synergistically combine the properties of their individual com-
ponents and furthermore allow biological and/or chemical limi-
tations and disadvantages of the individual starting materials
to be overcome. A well-established peptide-based ligand (L)
that induces cell adhesion is the tripeptidic sequence RGD (7;
R=arginine, G=glycine, D=aspartic acid). It strongly interacts
with integrins on the cell surface when forced into the correct
conformation, especially when it is part of a cyclic pentapep-
tide architecture (commonly cyclic RGDfK or cRGDfK).[21,22] Re-
cently, complex RGD assemblies have been constructed by or-
thogonal chemoselective ligation.[23,24]
Gel-like biomaterials play a key role as supports in regenerative
medicine.[1–4] Hydrogels based on biomacromolecules have
emerged as important scaffold materials, particularly in the
field of tissue engineering.[5–11] For clinical applications, bio-
compatibility is crucial to avoid immunogenic responses. Be-
sides polylactic acid, several polysaccharides such as alginate
(1) and hyaluronic acid (2) are important biomacromolecules
that have been widely investigated as scaffold materials with
advantageous properties concerning immunogenicity as well
as options for further functionalization.[12–15] Several polysac-
charides are widely used as blends to adjust their physical, me-
chanical and biological properties.[16–18]
The biocompatibility of these scaffold materials can be im-
proved by attaching additional (bio)functional groups to the
biomaterial.[19] By establishing a chemically defined modifica-
Herein, we disclose a synthetic toolbox for the flexible crea-
tion of modified polysaccharide strands, based on readily avail-
able polysaccharides. These polysaccharides are equipped with
a clickable functional group such as aldehyde or hydrazide.[14,25]
This toolbox is based on our preliminary investigations of new
biomaterials for use in tissue engineering,[13,15] and, here, we
extend the concept in a comprehensive study on the six poly-
saccharides alginate (1), hyaluronic acid (2), dextran (3), pullu-
lan (4), glycogen (5), and cellulose (6; Figure 1).
In principle, the chemistry chosen should allow either of the
two functional groups (aldehyde and hydrazide) to be intro-
duced into any of the chosen polysaccharides. Furthermore,
a biologically relevant ligand (L), namely, cRGDfK (7), was plan-
[a] N. Dibbert, Dr. A. Krause, Prof. Dr. A. Kirschning, Dr. G. Drꢀger
Institut fꢁr Organische Chemie und Biomolekulares Wirkstoffzentrum
(BMWZ), Leibniz Universitꢀt Hannover
Schneiderberg 1B, 30167 Hannover (Germany)
[b] J.-C. Rios-Camacho, Dr. I. Gruh
Leibniz Research Laboratories for Biotechnology and Artificial Organs
(LEBAO), Department of Cardiac, Thoracic, Transplant and Vascular Surgery
Hannover Medical School, Carl-Neuberg-Strasse 1
30659 Hannover (Germany)
Supporting information for this article is available on the WWW under
Chem. Eur. J. 2016, 22, 1 – 11
1
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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