Calcium phosphates compounds in conjunction with hydrogel as carrier for BMP-2: A study on ectopic bone formation in rats

Hulsart‐Billström, Gry; Hu, Qinghong; Bergman, Kristoffer; Jonsson, Kenneth B.; Åberg, Jonas; Tang, Ruikang; Larsson, Sune; Hilborn, Jöns

doi:10.1016/j.actbio.2011.04.021

Cited by 54 publications

(37 citation statements)

References 42 publications

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“…Misra et al incorporated nanosized and microsized bioglass particles into solid poly(3‐hydroxybutyrate) films and observed higher mineral formation and protein adsorption on films containing nano‐sized particles . Hulsart‐Billström et al implanted hydrogels loaded with bone morphogenetic protein‐2 and nanosized or microsized hydroxyapatite particles into rat quadriceps muscle and found that density of bone formed was higher in the case of nanosized particles . However, it is not certain that differences in size would influence bone regeneration upon implantation in a bone defect.…”

Section: Resultsmentioning

confidence: 99%

High‐resolution synchrotron X‐ray analysis of bioglass‐enriched hydrogels

Gorodzha

Douglas

Samal

et al. 2016

J Biomedical Materials Res

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Enrichment of hydrogels with inorganic particles improves their suitability for bone regeneration by enhancing their mechanical properties, mineralizability, and bioactivity as well as adhesion, proliferation, and differentiation of bone-forming cells, while maintaining injectability. Low aggregation and homogeneous distribution maximize particle surface area, promoting mineralization, cell-particle interactions, and homogenous tissue regeneration. Hence, determination of the size and distribution of particles/particle agglomerates in the hydrogel is desirable. Commonly used techniques have drawbacks. High-resolution techniques (e.g., SEM) require drying. Distribution in the dry state is not representative of the wet state. Techniques in the wet state (histology, µCT) are of lower resolution. Here, self-gelling, injectable composites of Gellan Gum (GG) hydrogel and two different types of sol-gel-derived bioactive glass (bioglass) particles were analyzed in the wet state using Synchrotron X-ray radiation, enabling high-resolution determination of particle size and spatial distribution. The lower detection limit volume was 9 × 10(-5) mm(3) . Bioglass particle suspensions were also studied using zeta potential measurements and Coulter analysis. Aggregation of bioglass particles in the GG hydrogels occurred and aggregate distribution was inhomogeneous. Bioglass promoted attachment of rat mesenchymal stem cells (rMSC) and mineralization.

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Section: Resultsmentioning

confidence: 99%

High‐resolution synchrotron X‐ray analysis of bioglass‐enriched hydrogels

Gorodzha

Douglas

Samal

et al. 2016

J Biomedical Materials Res

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“…Based on its biocompatibility, HA and crosslinked HA products are used clinically as intra-articular injections to treat joint and cartilage diseases, including osteoarthritis [16]. In addition, HA-based hydrogels have been used for delivery of several growth factors, including basic fibroblast growth factor (FGF-2) [17], vascular endothelial growth factor (VEGF) [18] and BMP-2 [19–21]. However, when FGF-2 is delivered without stabilization under normal physiological conditions, it diffuses rapidly, undergoes proteolysis and consequently loses bioactivity [22].…”

Section: Introductionmentioning

confidence: 99%

Hyaluronic acid-based hydrogels functionalized with heparin that support controlled release of bioactive BMP-2

et al. 2012

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Bone morphogenetic protein-2 (BMP-2) is a potent osteoinductive factor, yet its clinical use is limited by a short biological half-life, rapid local clearance and propensity for side effects. Heparin (HP), a highly sulfated glycosaminoglycan (GAG) that avidly binds BMP-2, has inherent biological properties that may circumvent these limitations. Here, we compared hyaluronan-based hydrogels formulated to include heparin (Heprasil™) with similar gels without heparin (Glycosil™) for their ability to deliver bioactive BMP-2 in vitro and in vivo. The osteogenic activity of BMP-2 released from the hydrogels was evaluated by monitoring alkaline phosphatase (ALP) activity and SMAD 1/5/8 phosphorylation in mesenchymal precursor cells. The osteoinductive ability of these hydrogels was determined in a rat ectopic bone model by 2D radiography, 3D µ-CT and histological analyses at 8 weeks post-implantation. Both hydrogels sustain the release of BMP-2. Importantly, the inclusion of a small amount of heparin (0.3% w/w) attenuated release of BMP-2 and sustained its osteogenic activity for up to 28 days. In contrast, hydrogels lacking heparin released more BMP-2 initially but were unable to maintain BMP-2 activity at later time points. Ectopic bone-forming assays using transplanted hydrogels emphasized the therapeutic importance of the initial burst of BMP-2 rather than its long-term osteogenic activity. Thus, tuning the burst release phase of BMP-2 from hydrogels may be advantageous for optimal bone formation.

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“…Additionally, it is possible that HAP particles could be incorporated in the new bone. Limited remaining agglomerates of HAP were seen after 4 weeks in earlier studies with a similar HYA–PVA–rhBMP‐2–HAP compound injected in thigh muscle of rats (Hulsart‐Billstrom et al ., ). De Groot () showed that degradation of large HAP implants was almost nil, as only a few microns of HAP had dissolved during a year; however, small HAP particles, similar to those included in the material examined in the present study, were significantly reduced in volume in a year.…”

Section: Discussionmentioning

confidence: 98%

A uni-cortical femoral defect model in the rat: evaluation using injectable hyaluronan hydrogel as a carrier for bone morphogenetic protein-2

Hulsart‐Billström

Bergman

Andersson

et al. 2012

J Tissue Eng Regen Med

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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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Calcium phosphates compounds in conjunction with hydrogel as carrier for BMP-2: A study on ectopic bone formation in rats

Cited by 54 publications

References 42 publications

High‐resolution synchrotron X‐ray analysis of bioglass‐enriched hydrogels

High‐resolution synchrotron X‐ray analysis of bioglass‐enriched hydrogels

Hyaluronic acid-based hydrogels functionalized with heparin that support controlled release of bioactive BMP-2

A uni-cortical femoral defect model in the rat: evaluation using injectable hyaluronan hydrogel as a carrier for bone morphogenetic protein-2

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