Hydrogel mechanical properties are more important than osteoinductive growth factors for bone formation with MSC spheroids

ABSTRACTMesenchymal stromal cells (MSCs) can promote tissue repair in regenerative medicine, and their therapeutic potential is further enhanced via spheroid formation. We demonstrated that intraspheroidal presentation of Bone Morphogenetic Protein-2 (BMP-2) on hydroxyapatite (HA) nanoparticles resulted in more spatially uniform MSC osteodifferentiation, providing a method to internally influence spheroid phenotype. Stress relaxation of hydrogels has emerged as a potent stimulus to enhance monodispersed MSC spreading and osteogenic differentiation, but the effect of hydrogel viscoelasticity on MSC spheroids has not been reported. Herein, we describe a materials-based approach to augment the osteogenic potential of entrapped MSC spheroids by leveraging the mechanical properties of alginate hydrogels. Compared to spheroids entrapped in covalently crosslinked, elastic alginate, calcium deposition of MSC spheroids was consistently increased in ionically crosslinked, viscoelastic alginate. We observed significant increases in calcium deposition by MSC spheroids loaded with BMP-2-HA in viscoelastic gels compared to soluble BMP-2, which was higher than all elastic alginate gels. Upon implantation in critically sized calvarial bone defects, we observed enhanced bone formation in all animals treated with viscoelastic hydrogels. Increases in bone formation were evident in viscoelastic gels, regardless of the mode of presentation of BMP-2 (i.e., soluble delivery or HA nanoparticles). These studies demonstrate that the dynamic mechanical properties of viscoelastic alginate are an effective strategy to enhance the therapeutic potential of MSC spheroids for bone formation and repair.

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Bone formation promoted by bone morphogenetic protein-2 plasmid-loaded porous silica nanoparticles with the involvement of autophagy

Nanoscale ◽

10.1039/c9nr07017f ◽

2019 ◽

Vol 11 (45) ◽

pp. 21953-21963 ◽

Cited By ~ 2

Author(s):

Xiaowei Xu ◽

Maolei Sun ◽

Dandan Wang ◽

Wenhuan Bu ◽

Zilin Wang ◽

...

Keyword(s):

Bone Formation ◽

Osteogenic Differentiation ◽

Silica Nanoparticles ◽

Bone Morphogenetic Protein ◽

Porous Silica ◽

Bone Morphogenetic Protein 2 ◽

Calcium Deposition ◽

Morphogenetic Protein

Bone morphogenetic protein-2 plasmid was encapsulated by polyethylenimine-modified porous silica nanoparticles, which promoted osteogenic differentiation and increased calcium deposition with the involvement of autophagy.

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Comparison of Recombinant Growth/Differentiation Factor-5 (rGDF-5) and Bone Morphogenetic Protein-2 (rBMP-2) in the In Vivo Bone Formation in Porous Hydroxyapatite Ceramic

Key Engineering Materials ◽

10.4028/www.scientific.net/kem.284-286.945 ◽

2005 ◽

Vol 284-286 ◽

pp. 945-948

Author(s):

H. Shimaoka ◽

Y. Dohi ◽

K. Narikawa ◽

Hajime Ohgushi ◽

M. Ikeuchi ◽

...

Keyword(s):

Growth Factors ◽

Bone Formation ◽

Bone Morphogenetic Protein ◽

De Novo ◽

Bone Morphogenetic Protein 2 ◽

Osteogenic Potential ◽

Differentiation Factor ◽

Morphogenetic Protein ◽

Growth Differentiation Factor 5

Various recombinant growth factors have been used for promoting osteoblastic differentiation cascade. To compare the growth/differentiation factor-5 (GDF-5) and bone morphogenetic protein-2 (BMP-2) in the in vivo osteogenic potential of bone marrow mesenchymal stem cells (MSCs), the bone formation was assessed by rat subcutaneous implantation of 5 kinds of hydroxyapatite (HA) implants; namely GDF/HA composites, BMP/HA composites, MSCs/HA composites and the MSCs/HA composites supplemented with recombinant mouse GDF-5 (GDF/MSCs/HA) or recombinant human BMP-2 (BMP/MSCs/HA). Neither the GDF/HA nor the BMP/HA composites exhibited any bone formation at any time after implantation. At both 2 and 4 weeks after implantation, obvious de novo bone formation together with active osteoblasts was seen histologically in many pores of the GDF/MSCs/HA and BMP/MSCs/HA composites. The GDF/MSCs/HA and BMP/MSCs/HA composites also showed high alkaline phosphatase (ALP) and osteocalcin expression determined at both the protein and gene levels. Compared with GDF/MSCs/HA, the BMP/MSCs/HA composites exhibited excellent osteogenesis with relatively early osteoblastic phenotype expression. These findings indicate that the two growth factors synergistically enhance de novo bone formation capability of MSCs/HA composites and the importance of ceramic surface to retain and to deliver the molecules of growth factors for the cell differentiation and maturation.

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Inkjet-Based Biopatterning of Bone Morphogenetic Protein-2 to Spatially Control Calvarial Bone Formation

Tissue Engineering Part A ◽

10.1089/ten.tea.2009.0650 ◽

2010 ◽

Vol 16 (5) ◽

pp. 1749-1759 ◽

Cited By ~ 79

Author(s):

Gregory M. Cooper ◽

Eric D. Miller ◽

Gary E. DeCesare ◽

Arvydas Usas ◽

Emily L. Lensie ◽

...

Keyword(s):

Bone Formation ◽

Bone Morphogenetic Protein ◽

Bone Morphogenetic Protein 2 ◽

Calvarial Bone ◽

Morphogenetic Protein

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The Bone Regeneration Capacity of BMP-2 + MMP-10 Loaded Scaffolds Depends on the Tissue Status

Pharmaceutics ◽

10.3390/pharmaceutics13070979 ◽

2021 ◽

Vol 13 (7) ◽

pp. 979

Author(s):

Patricia Garcia-Garcia ◽

Ricardo Reyes ◽

José Antonio Rodriguez ◽

Tomas Martín ◽

Carmen Evora ◽

...

Keyword(s):

Bone Formation ◽

Bone Regeneration ◽

Growth Promotion ◽

Tissue Growth ◽

Bone Morphogenetic Protein 2 ◽

Morphogenetic Protein ◽

Therapeutic Molecules ◽

Positive Effect

Biomaterials-mediated bone formation in osteoporosis (OP) is challenging as it requires tissue growth promotion and adequate mineralization. Based on our previous findings, the development of scaffolds combining bone morphogenetic protein 2 (BMP-2) and matrix metalloproteinase 10 (MMP-10) shows promise for OP management. To test our hypothesis, scaffolds containing BMP-2 + MMP-10 at variable ratios or BMP-2 + Alendronate (ALD) were prepared. Systems were characterized and tested in vitro on healthy and OP mesenchymal stem cells and in vivo bone formation was studied on healthy and OP animals. Therapeutic molecules were efficiently encapsulated into PLGA microspheres and embedded into chitosan foams. The use of PLGA (poly(lactic-co-glycolic acid)) microspheres as therapeutic molecule reservoirs allowed them to achieve an in vitro and in vivo controlled release. A beneficial effect on the alkaline phosphatase activity of non-OP cells was observed for both combinations when compared with BMP-2 alone. This effect was not detected on OP cells where all treatments promoted a similar increase in ALP activity compared with control. The in vivo results indicated a positive effect of the BMP-2 + MMP-10 combination at both of the doses tested on tissue repair for OP mice while it had the opposite effect on non-OP animals. This fact can be explained by the scaffold’s slow-release rate and degradation that could be beneficial for delayed bone regeneration conditions but had the reverse effect on healthy animals. Therefore, the development of adequate scaffolds for bone regeneration requires consideration of the tissue catabolic/anabolic balance to obtain biomaterials with degradation/release behaviors suited for the existing tissue status.

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