| 1. |
- Hulsart-Billström, Gry, et al.
(författare)
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A uni-cortical femoral defect model in the rat : evaluation using injectable hyaluronan hydrogel as a carrier for bone morphogenetic protein-2
- 2015
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Ingår i: Journal of Tissue Engineering and Regenerative Medicine. - : Hindawi Limited. - 1932-6254 .- 1932-7005. ; 9:7, s. 799-807
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Tidskriftsartikel (refereegranskat)abstract
- The development of biomaterial for bone regeneration requires animal models that are reliable and designed to mimic clinically relevant situations. We have previously investigated hydrogels comprised of modified hyaluronic acid and polyvinyl alcohol in models of ectopic bone formation. This hydrogel induces bone regeneration when loaded with bone morphogenetic proteins (BMPs). To allow further optimization of hydrogels, we developed a new, femoral, non-critical-sized cortical defect model. In the rat femur, we drilled standardized, elongated unilateral cortical defects that did not require stabilization and that could be created bilaterally to allow paired comparisons of biomaterials. After optimizing the defect size, subsequent stress fractures occurred in only 8% and the defect healed partially over the 40 day study period. In a time-course experiment, we treated bone defects with the previously studied hyaluronan hydrogel loaded with 10 µg hydroxyapatite and 6 µg BMP-2. The shape of the defect allowed controlled containment of the material within the defect. The defect in the right leg was left untreated, while the left defect was filled with 40 µl of the BMP hydrogel. As determined by pQCT analysis, the treated defects had a higher bone mineral content, bone area and bone density than control defects. The relative difference was greatest between the groups at 10 and 20 days and diminished as the defect healed in the untreated legs. We conclude that this animal model allows facile and rapid screening of biomaterials for bone regeneration in cortical femoral defects without requiring external fixation.
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| 2. |
- Hulsart-Billström, Gry, et al.
(författare)
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Calcium phosphates compounds in conjunction with hydrogel as carrier for BMP-2 : A study on ectopic bone formation in rats
- 2011
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Ingår i: Acta Biomaterialia. - : Elsevier BV. - 1742-7061 .- 1878-7568. ; 7:8, s. 3042-3049
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Tidskriftsartikel (refereegranskat)abstract
- Current treatment of fractures often involves the use of bone graft or bone morphogenetic proteins (BMP) to induce fracture healing, especially in patients with a compromised healing capacity. BMP has to be delivered in conjunction with a carrier. Unfortunately, there are drawbacks and limitations with current carriers, including their bovine origin which carries the risk of an immunological response. The physical properties also limit the use to open surgical procedures, as it cannot be injected. New carriers with improved properties are therefore needed. The aim of this study was to assess the ectopic bone forming capability of various calcium phosphate compounds when used in conjunction with a hydrogel as the carrier for BMP-2. Five different ceramic additives were tested, including beta-tricalcium phosphate and four types of hydroxyapatite (HAP) (nanoHAP, HAP, clods of HAP >100 mu m, and the biomimetic HAP Ostim35 (R)). The compounds were injected into the thigh muscle of rats, where it formed a gel in situ. After 4 weeks bone formation was evaluated by peripheral quantitative computed tomography and histology. The major finding was that the 20 nm nanoHAP yielded a higher bone density than the other additives (P = 0.0008, ANOVA with Tukey's multiple comparison test). We hypothesize that the higher bone density induced by nanoHAP might be due to nanocrystals of calcium phosphate acting as direct building blocks for biomineralization.
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| 3. |
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| 4. |
- Hulsart-Billström, Gry, et al.
(författare)
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Morphological differences in BMP-2-induced ectopic bone between solid and crushed hyaluronan hydrogel templates
- 2013
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Ingår i: Journal of materials science. Materials in medicine. - : Springer Science and Business Media LLC. - 0957-4530 .- 1573-4838. ; 24:5, s. 1201-1209
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Tidskriftsartikel (refereegranskat)abstract
- The possibility to affect bone formation by using crushed versus solid hydrogels as carriers for bone morphogenetic protein 2 (BMP-2) was studied. Hydrogels, based on chemical crosslinking between hyaluronic acid and poly(vinyl alcohol) derivatives, were loaded with BMP-2 and hydroxyapatite. Crushed and solid forms of the gels were analyzed both in vitro via a release study using I-125 radioactive labeling of BMP-2, and in vivo in a subcutaneous ectopic bone model in rats. Dramatically different morphologies were observed for the ectopic bone formed in vivo in the two types of gels, even though virtually identical release profiles were observed in vitro. Solid hydrogels induced formation of a dense bone shell around non-degraded hydrogel, while crushed hydrogels demonstrated a uniform bone formation throughout the entire sample. These results suggest that by crushing the hydrogel, the construct's three-dimensional network becomes disrupted. This could expose unreacted functional groups, making the fragment's surfaces reactive and enable limited chemical fusion between the crushed hydrogel fragments, leading to similar in vitro release profiles. However, in vivo these interactions could be broken by enzymatic activity, creating a macroporous structure that allows easier cell infiltration, thus, facilitating bone formation.
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| 5. |
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| 6. |
- Hulsart Billström, Gry, 1982-, et al.
(författare)
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Non-invasive tri-modal visualisation via PET/SPECT/μCT of recombinant human bone morphogenetic protein-2 retention and associated bone regeneration : A proof of concept
- 2018
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Ingår i: Journal of Controlled Release. - : Elsevier BV. - 0168-3659 .- 1873-4995. ; 285, s. 178-186
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Tidskriftsartikel (refereegranskat)abstract
- Bone morphogenetic proteins (BMP's) are vital for bone and cartilage formation, where bone morphogenetic protein-2 (BMP-2) is acknowledged as a growth factor in osteoblast differentiation. However, uncontrolled delivery may result in adverse clinical effects. In this study we investigated the possibility for longitudinal and non-invasive monitoring of implanted [125I]BMP-2 retention and its relation to ossification at the site of implantation. A unilateral critically sized femoral defect was produced in the left limb of rats while the right femur was retained intact as a paired reference control. The defect was filled with a hyaluronan hydrogel with 25% hydroxyapatite alone (carrier control; n = 2) or combined with a mixture of [125I]BMP-2 (150 μg/ml; n = 4). Bone formation was monitored using micro computed tomography (μCT) scans at 1, 3, 5, 7, 9 and 12 weeks. The retention of [125I]BMP-2 was assessed with single photon emission computed tomography (SPECT), and the bone healing process was followed with sodium fluoride (Na18F) using positron emission tomography (PET) at day 3 and at week 2, 4, and 6. A rapid burst release of [125I]BMP-2 was detected via SPECT. This was followed by a progressive increase in uptake levels of [18F]fluoride depicted by PET imaging that was confirmed as bone formation via μCT. We propose that this functional, non-invasive imaging method allows tri-modal visualisation of the release of BMP-2 and the following in vivo response. We suggest that the potential of this novel technique could be considered for preclinical evaluation of novel smart materials on bone regeneration.
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| 8. |
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| 9. |
- Stenfelt, Sonya, et al.
(författare)
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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
- 2014
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Ingår i: Journal of materials science. Materials in medicine. - : Springer Science and Business Media LLC. - 0957-4530 .- 1573-4838. ; 25:4, s. 1013-1023
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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