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Hyaluronan Derivatives and Injectable Gels for Tissue Engineering
Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för materialkemi.
2008 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

The present work describes the preparation of hyaluronan derivatives and hydrogels with potential use in tissue engineering applications. A potentially injectable hydrogel consisting of hyaluronan and collagen was successfully used to grow neurons in vitro by encapsulation of neural stem and progenitor cells. Attempts were further made to establish a suitable modification strategy which could be used for the preparation of in vivo cross-linkable hyaluronan derivatives. The synthesis of a model substance consisting of a D-glucuronate derivative which could simplify the development of such a modification technique is described, although a new method to prepare hyaluronan derivatives was found without its use. The modification strategy involves the use of a triazine-reagent which enables the covalent attachment of hydrophilic and hydrophobic amines to hyaluronan carboxyl groups in a controlled fashion under mild conditions. Using triazine-activated amidation we synthesized an aldehyde-derivative of hyaluronan which was used to prepare gels by cross-linking with hydrazide-modified polyvinyl-alcohol. Gels were formed in less than 1 minute by mixing equal volumes of the polymer derivatives and they were subsequently used as a carrier for bone morphogenetic protein-2. An in vitro release study showed that approximately 88% of the growth factor is retained in the gel over a 4 week period. The ability to form new bone in vivo was further evaluated in an ectopic rat model by the injection of gels containing 30 µg BMP-2. Radiographic and histological examination 4 and 10 weeks after injection showed the formation of new bone without any signs of inflammation or foreign body response. Hydroxyapatite particles were further added to improve the mechanical properties of the gel, and a comparative study was conducted. This time the induced tissue consisted not only of bone, but also of interconnected cartilage and tendon, as confirmed by histology and immunohistochemistry.

Ort, förlag, år, upplaga, sidor
Uppsala: Universitetsbiblioteket , 2008. , s. 51
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 573
Nyckelord [en]
Hyaluronan, Hydrogel, Tissue Engineering, Scaffold, Minimally invasive strategy, Bone morphogenetic protein, Hydroxyapatite, Bone, Cartilage, Tendon
Nationell ämneskategori
Polymerkemi
Identifikatorer
URN: urn:nbn:se:uu:diva-9357ISBN: 978-91-554-7335-8 (tryckt)OAI: oai:DiVA.org:uu-9357DiVA, id: diva2:172782
Disputation
2008-12-05, Polhemsalen, Ångströmlaboratoriet, Lägerhyddsvägen 1, Uppsala, 09:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2008-11-14 Skapad: 2008-11-14 Senast uppdaterad: 2010-03-04Bibliografiskt granskad
Delarbeten
1. Enhanced neuronal differentiation in a three-dimensional collagen-hyaluronan matrix
Öppna denna publikation i ny flik eller fönster >>Enhanced neuronal differentiation in a three-dimensional collagen-hyaluronan matrix
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2007 (Engelska)Ingår i: Journal of Neuroscience Research, ISSN 0360-4012, E-ISSN 1097-4547, Vol. 85, nr 10, s. 2138-2146Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Efficient 3D cell systems for neuronal induction are needed for future use in tissue regeneration. In this study, we have characterized the ability of neural stem/progenitor cells (NS/PC) to survive, proliferate, and differentiate in a collagen type I-hyaluronan scaffold. Embryonic, postnatal, and adult NS/PC were seeded in the present 3D scaffold and cultured in medium containing epidermal growth factor and fibroblast growth factor-2, a condition that stimulates NS/PC proliferation. Progenitor cells from the embryonic brain had the highest proliferation rate, and adult cells the lowest, indicating a difference in mitogenic responsiveness. NS/PC from postnatal stages down-regulated nestin expression more rapidly than both embryonic and adult NS/PC, indicating a faster differentiation process. After 6 days of differentiation in the 3D scaffold, NS/PC from the postnatal brain had generated up to 70% neurons, compared with 14% in 2D. NS/PC from other ages gave rise to approximately the same proportion of neurons in 3D as in 2D (9-26% depending on the source for NS/PC). In the postnatal NS/PC cultures, the majority of III-tubulin-positive cells expressed glutamate, -aminobutyric acid, and synapsin I after 11 days of differentiation, indicating differentiation to mature neurons. Here we report that postnatal NS/PC survive, proliferate, and efficiently form synapsin I-positive neurons in a biocompatible hydrogel.

Nyckelord
3D cultures, neural stem/progenitor cells, hydrogel, scaffold, neurogenesis
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:uu:diva-11683 (URN)10.1002/jnr.21358 (DOI)000248516700008 ()17520747 (PubMedID)
Tillgänglig från: 2007-10-17 Skapad: 2007-10-17 Senast uppdaterad: 2017-12-11Bibliografiskt granskad
2. Selective Michael-type addition of a D-glucuronic acid derivative in the synthesis of model substances for uronic acid containing polysaccharides
Öppna denna publikation i ny flik eller fönster >>Selective Michael-type addition of a D-glucuronic acid derivative in the synthesis of model substances for uronic acid containing polysaccharides
2008 (Engelska)Ingår i: Express Polymer Letters, ISSN 1788-618X, Vol. 2, nr 8, s. 553-559Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

A flexible protocol for the preparation of model substances for uronic acid containing polysaccharides is presented.We have synthesized a D-glucuronic acid derivative which is designed so that it easily can be conjugated with differentstructures and architectures by selective Michael-type addition. By successful coupling of the glucuronic acidderivative to polyethylene glycol with high degree of conversion, products were obtained that were easily characterized andwhich resembled polysaccharides in terms of solubility and purification methods that could be employed. The model substancecan potentially be used to facilitate optimization of low-degree modification reactions of high molecular weightD-glucuronic acid containing polysaccharides.

Nyckelord
polymer gels, polysaccharides, Michael-type addition, model substance, NMR
Nationell ämneskategori
Polymerkemi
Identifikatorer
urn:nbn:se:uu:diva-97728 (URN)10.3144/expresspolymlett.2008.67 (DOI)000263687000004 ()
Tillgänglig från: 2008-11-14 Skapad: 2008-11-14 Senast uppdaterad: 2010-08-25Bibliografiskt granskad
3. Hyaluronic acid derivatives prepared in aqueous media by triazine-activated amidation
Öppna denna publikation i ny flik eller fönster >>Hyaluronic acid derivatives prepared in aqueous media by triazine-activated amidation
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2007 (Engelska)Ingår i: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 8, nr 7, s. 2190-2195Artikel i tidskrift (Refereegranskat) Published
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.

Nyckelord
Oside polymer, Experimental study, Mild operating conditions, Aqueous medium, Triazine derivatives, Activation, Primary amine, Amidation, Chemical modification, Preparation, Modified material, Hyaluronic acid
Nationell ämneskategori
Kemi
Identifikatorer
urn:nbn:se:uu:diva-97729 (URN)10.1021/bm0701604 (DOI)000247820000022 ()17579475 (PubMedID)
Tillgänglig från: 2008-11-14 Skapad: 2008-11-14 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
4. Injectable cell-free template for bone-tissue formation
Öppna denna publikation i ny flik eller fönster >>Injectable cell-free template for bone-tissue formation
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2009 (Engelska)Ingår i: Journal of Biomedical Materials Research-Part A, ISSN 1549-3296, Vol. 91A, nr 4, s. 1111-1118Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Here we present a novel injectable hydrogel which forms a template for de novo formation of bone tissue. Hydrogel formation takes place in situ in less than 1 min by the cross-linking of multifunctional hyaluronic acid and polyvinyl alcohol derivatives. Endogenous cells are recruited in vivo by incorporating bone morphogenetic protein-2 (BMP-2), a powerful promoter for osteogenic differentiation. The hydrogel was evaluated in vitro by performing a cell viability test and a release study and in vivo by a rat ectopic model. Examination by X-ray, microcomputed tomography, and histology revealed a significant bone formation at the target site for gels containing BMP-2, and a complete degradation was observed for gels without BMP-2 four weeks after injection. There were no signs of inflammation or foreign body response in either group and we believe that this system has the potential as an off-the-shelf injectable to be used where bone tissue is needed.

Ort, förlag, år, upplaga, sidor
Wiley Periodicals, Inc, 2009
Nyckelord
hydrogel, hyaluronan, injectable, bone tissue engineering, bone morphogenetic protein, polyvinyl alcohol
Nationell ämneskategori
Kemi
Forskningsämne
Oorganisk kemi
Identifikatorer
urn:nbn:se:uu:diva-97730 (URN)10.1002/jbm.a.32289 (DOI)000272196900017 ()
Tillgänglig från: 2008-11-14 Skapad: 2008-11-14 Senast uppdaterad: 2010-06-23Bibliografiskt granskad
5. Ectopic induction of the tendon-bone interface
Öppna denna publikation i ny flik eller fönster >>Ectopic induction of the tendon-bone interface
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Artikel i tidskrift (Refereegranskat) Submitted
Identifikatorer
urn:nbn:se:uu:diva-97731 (URN)
Tillgänglig från: 2008-11-14 Skapad: 2008-11-14Bibliografiskt granskad

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