Abstract
The aim of the present study was to evaluate the effect of different dosages of retarded vs. rapid release of bone morphogenic protein 2 (BMP2) at different recipient sites. Porous composite poly(D,L-lactic acid) (PDLLA)/CaCO3 scaffolds were loaded with three different dosages of rhBMP2 (24 µg, 48 µg and 96 µg) and implanted, together with blank controls, both into non-healing defects of the mandibles and into the gluteal muscles of 24 adult male Wistar rats. After 26 weeks, bone formation and expression of bone specific markers [alkaline phosphatase (AP) and Runx2] were evaluated by histomorphometry and immunohistochemistry. Results showed that the mode of delivery had no quantitative effect on bone formation in mandibular sites. Expression of AP and Runx2 showed significant differences among the three dosage groups. There were significant correlations between the expression of both AP and Runx2 as well as the extent of bone formation, with both retarded and rapid release of rhBMP2. In ectopic sites, retarded release significantly enhanced bone formation in the low and medium dosage groups, compared to rapid release. Expression of AP was significantly higher and Runx2 significantly lower in ectopic sites, compared to mandibular sites. Significant correlations between the expression of bone specific markers and bone formation occurred only in the retarded delivery groups, but not in the rapid release groups. Within the limitations of the experimental model, it was concluded that retarded delivery of BMP2 was effective, preferably in sites with low or non-existing pristine osteogenic activity. Expression of bone specific markers indicated that osteogenic pathways might be different in mandibular vs. ectopic sites.
Highlights
Bone growth factors (BMPs), namely bone morphogenic protein 2 (BMP2) and BMP7, have been in clinical use for several years with a variety of indications (Kelly et al, 2016; Delawi et al, 2016; Friedländer et al, 2001; Buttermann, 2008)
The curve fitting resulted in an estimated delivery from the retarded release carriers of 2.40-5.08 μg of rhBMP2 after 26 weeks, whereas the delivery from the rapid release carriers was calculated not to increase above that amount delivered after 5 weeks – varying between 12.69 and 79.01 μg of rhBMP2, according to the initial dosage applied (Fig. 4c,d)
Bone induced by retarded delivery carriers was more evenly distributed across the carrier cross section than in rapid release carriers, where bone formation in the low and medium dosage groups occurred in smaller amounts, mainly at the periphery of the carrier
Summary
Bone growth factors (BMPs), namely BMP2 and BMP7, have been in clinical use for several years with a variety of indications (Kelly et al, 2016; Delawi et al, 2016; Friedländer et al, 2001; Buttermann, 2008). One reason for the use of supraphysiological dosages is the insufficient mode of delivery, indicating the need for the development of controlled-release carriers to reduce the applied dosages. This has prompted extensive research efforts, with a large variety of materials being tested and validated (for review see Kanczler and Oreffo, 2008; Gothard et al, 2014). Alongside this large body of research, experimental reports indicate that retarded release may be of little effect with regard to the amount of bone generated (Gruber et al, 2015; Geuze et al, 2012). The reaction to different release kinetics of bone growth factors may be site specific, with respect to orthotopic vs. ectopic sites (Kempen et al, 2009; Patel et al, 2008)
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