TY - JOUR
T1 - Effect of local sequential VEGF and BMP-2 delivery on ectopic and orthotopic bone regeneration
AU - Kempen, Diederik H.R.
AU - Lu, Lichun
AU - Heijink, Andras
AU - Hefferan, Theresa E.
AU - Creemers, Laura B.
AU - Maran, Avudaiappan
AU - Yaszemski, Michael J.
AU - Dhert, Wouter J.A.
N1 - Funding Information:
The authors wish to thank Dr. Wang and Mr. Greutzmacher from the Tissue Engineering and Biomaterials Laboratory for their assistance with polymer chemistry, Dr. Ritman, Mrs. Beighley and Mr. Vercnocke from the Physiological Imaging Research Laboratory for their assistance with μCT imaging, and Mrs. Burges and Mr. Herrick from the Bone Histomorphometry Laboratory for their assistance with histology. This study was supported by the National Institutes of Health (R01 AR45871 and R01 EB03060) and The Netherlands Organization for Health Research and Development (ZonMW).
PY - 2009/5
Y1 - 2009/5
N2 - Bone regeneration is a coordinated cascade of events regulated by several cytokines and growth factors. Angiogenic growth factors are predominantly expressed during the early phases for re-establishment of the vascularity, whereas osteogenic growth factors are continuously expressed during bone formation and remodeling. Since vascular endothelial growth factor (VEGF) and bone morphogenetic proteins (BMPs) are key regulators of angiogenesis and osteogenesis during bone regeneration, the aim of this study was to investigate if their sequential release could enhance BMP-2-induced bone formation. A composite consisting of poly(lactic-co-glycolic acid) microspheres loaded with BMP-2 embedded in a poly(propylene) scaffold surrounded by a gelatin hydrogel loaded with VEGF was used for the sequential release of the growth factors. Empty composites or composites loaded with VEGF and/or BMP-2 were implanted ectopically and orthotopically in Sprague-Dawley rats (n = 9). Following implantation, the local release profiles were determined by measuring the activity of 125I-labeled growth factors using scintillation probes. After 8 weeks blood vessel and bone formation were analyzed using microangiography, μCT and histology. The scaffolds exhibited a large initial burst release of VEGF within the first 3 days and a sustained release of BMP-2 over the full 56-day implantation period. Although VEGF did not induce bone formation, it did increase the formation of the supportive vascular network (p = 0.03) in ectopic implants. In combination with local sustained BMP-2 release, VEGF significantly enhanced ectopic bone formation compared to BMP-2 alone (p = 0.008). In the orthotopic defects, no effect of VEGF on vascularisation was found, nor was bone formation higher by the combination of growth factors, compared to BMP-2 alone. This study demonstrates that a sequential angiogenic and osteogenic growth factor release may be beneficial for the enhancement of bone regeneration.
AB - Bone regeneration is a coordinated cascade of events regulated by several cytokines and growth factors. Angiogenic growth factors are predominantly expressed during the early phases for re-establishment of the vascularity, whereas osteogenic growth factors are continuously expressed during bone formation and remodeling. Since vascular endothelial growth factor (VEGF) and bone morphogenetic proteins (BMPs) are key regulators of angiogenesis and osteogenesis during bone regeneration, the aim of this study was to investigate if their sequential release could enhance BMP-2-induced bone formation. A composite consisting of poly(lactic-co-glycolic acid) microspheres loaded with BMP-2 embedded in a poly(propylene) scaffold surrounded by a gelatin hydrogel loaded with VEGF was used for the sequential release of the growth factors. Empty composites or composites loaded with VEGF and/or BMP-2 were implanted ectopically and orthotopically in Sprague-Dawley rats (n = 9). Following implantation, the local release profiles were determined by measuring the activity of 125I-labeled growth factors using scintillation probes. After 8 weeks blood vessel and bone formation were analyzed using microangiography, μCT and histology. The scaffolds exhibited a large initial burst release of VEGF within the first 3 days and a sustained release of BMP-2 over the full 56-day implantation period. Although VEGF did not induce bone formation, it did increase the formation of the supportive vascular network (p = 0.03) in ectopic implants. In combination with local sustained BMP-2 release, VEGF significantly enhanced ectopic bone formation compared to BMP-2 alone (p = 0.008). In the orthotopic defects, no effect of VEGF on vascularisation was found, nor was bone formation higher by the combination of growth factors, compared to BMP-2 alone. This study demonstrates that a sequential angiogenic and osteogenic growth factor release may be beneficial for the enhancement of bone regeneration.
KW - Bone morphogenetic protein-2
KW - Bone regeneration
KW - Local release
KW - Vascular endothelial growth factor
KW - Vessel formation
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U2 - 10.1016/j.biomaterials.2009.01.031
DO - 10.1016/j.biomaterials.2009.01.031
M3 - Article
C2 - 19232714
AN - SCOPUS:61549132911
SN - 0142-9612
VL - 30
SP - 2816
EP - 2825
JO - Biomaterials
JF - Biomaterials
IS - 14
ER -