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Pre-incubation of chemically crosslinked hyaluronan-based hydrogels, loaded with BMP-2 and hydroxyapatite, and its effect on ectopic bone formation
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Materials Chemistry, Polymer Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science.
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2014 (English)In: Journal of materials science. Materials in medicine, ISSN 0957-4530, E-ISSN 1573-4838, Vol. 25, no 4, 1013-1023 p.Article in journal (Refereed) Published
Abstract [en]

The effects of pre-incubation of hyaluronan hydrogels, for different lengths of time after the initiation of chemical crosslinking and prior to injection, were explored both by investigating the in vitro BMP-2 release kinetics from the hydrogel and by studying the ectopic bone formation in rats. From the curing profile, obtained from rheological analysis, appropriate pre-incubation times (1 min, 5 h and 3 days) were selected, to prepare slightly, moderately and fully cured hydrogels. Comparable release profiles were observed for all three test groups in vitro. Furthermore, radiography, pQCT and histology of the explanted grafts showed cancellous bone formation in all groups after 5 weeks in vivo. However, longer pre-incubation times gave rise to an increase in bone volume, but a decrease in bone density. Moreover, the 5 h and the 3 days grafts appeared to be more ordered and resistant to deformation from the surrounding tissue than the 1 min grafts. The observed variations in mechanical and biological properties could potentially be used to adapt the treatment for a specific indication.

Place, publisher, year, edition, pages
2014. Vol. 25, no 4, 1013-1023 p.
National Category
Biomaterials Science
Research subject
Chemistry with specialization in Polymer Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-158963DOI: 10.1007/s10856-014-5147-yISI: 000333093300006OAI: oai:DiVA.org:uu-158963DiVA: diva2:441887
Available from: 2011-09-19 Created: 2011-09-19 Last updated: 2017-12-08Bibliographically approved
In thesis
1. Biomaterials for Promoting Self-Healing of Bone Tissue
Open this publication in new window or tab >>Biomaterials for Promoting Self-Healing of Bone Tissue
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The present work addresses poor bone/implant integration and severe bone defects. In both conditions external stimuli is required for new bone to form. A multilayered functional implant coating, comprised of an inner layer of crystalline titanium dioxide (TiO2) and an outer layer of hydroxyapatite (HAP), loaded with bone morphogenetic protein-2 (BMP-2), was proposed as a tool for providing both improved initial bone formation and long-term osseointegration. The in vitro characterization of the implant coatings showed that TiO2 and HAP were more favorable for cell viability, cell morphology and initial cell differentiation, compared to native titanium oxide. Furthermore, significantly higher cell differentiation was observed on surfaces with BMP-2, indicating that a simple soaking process can be used for incorporating bioactive molecules. Moreover, the results suggest that there could be a direct interaction between BMP-2 and HAP, which prolongs the retention of the growth factor, improving its therapeutic effect.

For treating severe bone defects a strategy involving BMP-2 delivery from hyaluronan hydrogels was explored. The hydrogels were prepared from two reactive polymers – an aldehyde-modified hyaluronan and a hydrazide-modified poly(vinyl alcohol). Upon mixing, the two components formed a chemically crosslinked hydrogel. In this work the mixing of the hydrogel components was optimized by rheological measurements. Furthermore, an appropriate buffer was selected for in vitro experiments by studying the swelling of hydrogels in PBS and in cell culture medium. A detection method, based on radioactive labeling of BMP-2 with 125I was used to monitor growth factor release both in vitro and in vivo. The results showed a biphasic release profile of BMP-2, where approximately 16 %  and 3 % of the growth factor remained inside the hydrogel after 4 weeks in vitro and in vivo, respectively. The initial fast release phase corresponded to the early ectopic bone formation observed 8 d after injection of the hydrogel formulation in the thigh muscle of rats. The hydrogel formulation could be improved by incorporation of HAP powder into the hydrogel formulation. Furthermore, bone formation could be increased by pre-incubation of the premixed hydrogel components inside the syringe prior to injection. Crushed hydrogels were also observed to induce more bone formation compared to solid hydrogels, when implanted subcutaneously in rats. This was thought to be due to increased surface area of the hydrogel, which allowed for improved cell infiltration.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2011. 70 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 857
Keyword
Osseointegration, implant coating, hyaluronan hydrogel, bone morphogenetic protein-2, hydroxyapatite, bone, delivery system, injectable, mixing, radioactive labeling
National Category
Biomaterials Science Polymer Chemistry
Research subject
Chemistry with specialization in Polymer Chemistry
Identifiers
urn:nbn:se:uu:diva-158939 (URN)978-91-554-8168-1 (ISBN)
Public defence
2011-11-11, Häggsalen, Ångströmlaboratoriet, Lägerhyddsvägen 1, Uppsala, 13:00 (English)
Opponent
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Available from: 2011-10-21 Created: 2011-09-19 Last updated: 2011-11-04Bibliographically approved

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Hulsart-Billström, GryGedda, LarsLarsson, SuneHilborn, JönsBowden, Tim

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