The effects of rhBMP-2 released from biodegradable polyurethane/microsphere composite scaffolds on new bone formation in rat femora

Department of Chemical and Biomolecular Engineering, Vanderbilt University, 2301 Vanderbilt Place, VU Station B #351604, Nashville, TN 37235, USA.
Biomaterials (Impact Factor: 8.56). 09/2009; 30(35):6768-79. DOI: 10.1016/j.biomaterials.2009.08.038
Source: PubMed


Scaffolds prepared from biodegradable polyurethanes (PUR) have been investigated as a supportive matrix and delivery system for skin, cardiovascular, and bone tissue engineering. While previous studies have suggested that PUR scaffolds are biocompatible and moderately osteoconductive, the effects of encapsulated osteoinductive molecules, such as recombinant human bone morphogenetic protein (rhBMP-2), on new bone formation have not been investigated for this class of biomaterials. The objective of this study was to investigate the effects of different rhBMP-2 release strategies on new bone formation in PUR scaffolds implanted in rat femoral plug defects. In the simplest approach, rhBMP-2 was added as a dry powder prior to the foaming reaction, which resulted in a burst release of 35% followed by a sustained release for 21 days. Encapsulation of rhBMP-2 in either 1.3-micron or 114-micron PLGA microspheres prior to the foaming reaction reduced the burst release. At 4 weeks post-implantation, all rhBMP-2 treatment groups enhanced new bone formation relative to the scaffolds without rhBMP-2. Scaffolds incorporating rhBMP-2 powder promoted the most extensive new bone formation, while scaffolds incorporating rhBMP-2 encapsulated in 1.3-micron microspheres, which exhibited the lowest burst release, promoted the least extensive new bone formation. Thus our observations suggest that an initial burst release followed by sustained release is better for promoting new bone formation.

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    • "– [262] [260] [261] [334] PGE 2 EP2 agonist – [243] – – – [240] [241] [242] PGE 2 EP4 agonist – – [239] [234] – [242] [245] Basic FGF – [61,62] [63,64,67] [335] [68,69] [59] [70] BMP-2 – [336,337] [338] – [25] [76] [77] [339] by fragility fractures. Local drug delivery could significantly reduce morbidity and healing time of osteoporotic fractures having the potential to reduce associated socioeconomic costs. "
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    ABSTRACT: Fragility fractures can cause significant morbidity and mortality in patients with osteoporosis and inflict considerable medical and socioeconomic burden. Moreover, treatment of an osteoporotic fracture is challenging due to the decreased strength of the surrounding bone and suboptimal healing capacity, predisposing both to fixation failure and non-union. Whereas a systemic osteoporosis treatment acts slowly, local release of osteogenic agents in osteoporotic fracture would act rapidly to increase bone strength and quality as well as to reduce the bone healing period and prevent development of a problematic non-union. The identification of agents with potential to stimulate bone formation and improve implant fixation strength in osteoporotic bone has raised hope for the fast augmentation of osteoporotic fractures. Stimulation of bone formation by local delivery of growth factors is an approach already in clinical use for the treatment of non-unions, and could be utilized for osteoporotic fractures as well. Small molecules have also gained ground as stable and inexpensive compounds to enhance bone formation and tackle osteoporosis. The aim of this paper is to present the state of the art on local drug delivery in osteoporotic fractures. Advantages, disadvantages and underlying molecular mechanisms of different active species for local bone healing in osteoporotic bone are discussed. This review also identifies promising new candidate molecules and innovative approaches for the local drug delivery in osteoporotic bone.
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    • "For many tissue engineering applications a sought after objective is the controlled and often prolonged release of growth factors in vivo (Lee et al., 2011). Conversely, in vivo studies have demonstrated the importance of a bolus release of BMPs for bone repair (Li et al., 2009). In light of these concepts, BMP-9 seems to be particularly effective. "
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    ABSTRACT: Bone morphogenetic proteins (BMPs) other than the clinically available BMP-2 and BMP-7 may be useful for improving fracture healing through both increasing osteogenesis and creating a favorable healing environment by altering cytokine release by endogenous cells. Given the spectrum of potential applications for BMPs, the objective of this study was to evaluate various BMPs under a variety of conditions to provide further insight into their therapeutic capabilities. The alkaline phosphatase (ALP) activity of both C2C12 and human adipose-derived stem cells (hASCs) was measured after exposure of increasing doses of recombinant human BMP-2, -4, -5, -6, -7, or -9 for 3 and 7 days. BMPs-2, -4, -5, -6, -7, and -9 were compared in terms of their ability to affect the release of stromal derived factor-1 (SDF-1), vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (b-FGF) from human bone marrow stromal cells (hBMSCs). Gene expression of ALP, osteocalcin, SDF-1, VEGF, and b-FGF following shRNA-mediated knockdown of BMP-2 and BMP-6 in hBMSCs or human osteoblasts under osteogenic differentiation conditions was also evaluated. Collectively, BMPs-6 and -9 produced the greatest osteogenic differentiation of C2C12 and hASCs as determined by ALP. The hBMSC secretion of SDF-1 was most affected by BMP-5, VEGF by BMP-4, and b-FGF by BMP-2. The knockdown of BMP-2 in BMSCs had no effect on any of the genes measured whereas BMP-6 knockdown in hBMSCs caused a significant increase in VEGF gene expression. BMP-2 and BMP-6 knockdown in human osteoblasts caused significant increases in VEGF gene expression and trends toward decreases in osteocalcin expression. These findings support efforts to study other BMPs as potential bone graft supplements, and to consider combined BMP delivery for promotion of multiple aspects of fracture healing.
    Full-text · Article · Oct 2013 · Frontiers in Pharmacology
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    • "Although a large number of studies have been performed, little attention has been paid to the optimal BMP-2 release profile to enhance in vivo osteogenic efficacy. Some authors report that longterm delivery with no or short burst release enhances the in vivo osteogenic efficacy of BMP-2 (Jeon et al., 2008), others suggest that a burst release followed by sustained release better promotes new bone formation (Li et al., 2009a; Brown et al., 2011). From our point of view, an appropriate GF dose, timing and sequence of signal presentation , and the physical–chemical and three-dimensional attributes of the scaffold are crucial to mimic the physiological repair process in bone. "
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    ABSTRACT: A concentric delivery system, composed of the three biomaterials SPU, PLGA, and βTCP (segmented polyurethane, poly[lactic-co-glycolic acid], and β-tricalcium phosphate) was fabricated as an external, porous ring of βTCP with a pasty core of a new SPU, mixed with PLGA microspheres. The regenerative effects of two distinct doses of either immediately available or continuously released rhBMP-2 were evaluated in an 8 mm, critical calvaria defect in rats. Protein dose and release kinetics affected material resorption rates and the progression of the regeneration process. Groups treated with the empty system alone or in conjunction with free rhBMP-2 did not respond. By contrast, after 12 weeks, approximately 20% and 60% of the defects implanted with systems loaded with 1.6 μg and 6.5 μg rhBMP-2, respectively were healed, with all the growth factor being released in the course of 6 weeks. The NMR, FTIR, GPC, DSC, and histological analyses showed that PLGA microsphere degradation occurred independently of the regenerative process. However, the resorption rate of the SPU and βTCP did depend on the regeneration process, which was governed by dose and release rate of rhBMP-2. Furthermore, the biocompatibility and high capacity of adaptation to the defect convert the herein proposed, new SPU polymer into a potential material for applications in tissue engineering and regenerative medicine.
    Full-text · Article · Jun 2013 · European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences
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