BMP-2 plasmid DNA-loaded chitosan films – A new strategy for bone engineering

Li, Juan; Lin, Jun; Yu, Wenke; Song, Xingguo; Hu, Qiaoling; Xu, Jinghong; Wang, Huiming; Mehl, Christian

doi:10.1016/j.jcms.2017.10.005

Cited by 10 publications

(3 citation statements)

References 53 publications

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“…The results at this early time-point are impressive as most previous studies do not show a similar level of healing until 6-8 weeks post-implantation [50,51]. Furthermore, the results are comparable to a recent study using chitosan films loaded with five times the dose of pBMP-2 (10 µg versus 2 µg used in this study) [52]. Another study using chitosan nanoparticles to deliver pBMP-2 within a chitosan hydrogel showed promising results although the defect was smaller (5 mm versus 7 mm in this study) and the methods used to determine new bone formation were qualitative rather than quantitative, making it difficult to draw comparisons [53].…”

Section: Discussionsupporting

confidence: 82%

Delivery of the improved BMP-2-Advanced plasmid DNA within a gene-activated scaffold accelerates mesenchymal stem cell osteogenesis and critical size defect repair

Raftery

Mencía-Castaño

Sperger

et al. 2018

Journal of Controlled Release

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Gene-activated scaffolds have been shown to induce controlled, sustained release of functional transgene both in vitro and in vivo. Bone morphogenetic proteins (BMPs) are potent mediators of osteogenesis however we found that the delivery of plasmid BMP-2 (pBMP-2) alone was not sufficient to enhance bone formation. Therefore, the aim of this study was to assess if the use of a series of modified BMP-2 plasmids could enhance the functionality of a pBMP-2 gene-activated scaffold and ultimately improve bone regeneration when implanted into a critical sized bone defect in vivo. A multi-cistronic plasmid encoding both BMP-2 and BMP-7 (BMP-2/7) was employed as was a BMP-2-Advanced plasmid containing a highly truncated intron sequence. With both plasmids, the highly efficient cytomegalovirus (CMV) promoter sequence was used. However, as there have been reports that the elongated factor 1-α promoter is more efficient, particularly in stem cells, a BMP-2-Advanced plasmid containing the EF1α promoter was also tested. Chitosan nanoparticles (CS) were used to deliver each plasmid to MSCs and induced transient up-regulation of BMP-2 protein expression, in turn significantly enhancing MSC-mediated osteogenesis when compared to untreated controls (p < 0.001). When incorporated into a bone mimicking collagen-hydroxyapatite scaffold, the BMP-2-Advanced plasmid, under the control of the CMV promotor, induced MSCs to produce approximately 2500 μg of calcium per scaffold, significantly higher (p < 0.001) than all other groups. Just 4 weeks post-implantation in vivo, this cell-free gene-activated scaffold induced significantly more bone tissue formation compared to a pBMP-2 gene-activated scaffold (p < 0.001) as indicated by microCT and histomorphometry. Immunohistochemistry revealed that the BMP-2-Advanced plasmid accelerated differentiation of osteoprogenitor cells to mature osteoblasts, thus causing rapid healing of the bone defects. This study confirms that optimising the plasmid construct can enhance the functionality of gene-activated scaffolds and translate to accelerated bone formation in a critical sized defect.

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Section: Discussionsupporting

confidence: 82%

Delivery of the improved BMP-2-Advanced plasmid DNA within a gene-activated scaffold accelerates mesenchymal stem cell osteogenesis and critical size defect repair

Raftery

Mencía-Castaño

Sperger

et al. 2018

Journal of Controlled Release

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“…CS-based scaffolds can maintain an osteoblast's normal activities, promote mineral rich matrix and tissue regeneration [ 12 ]. The ability to bind anionic molecules such as growth factors, GAG, DNA, rendered CS an effective strategy for guided bone regeneration [ 13 ]. Especially, CS linked with DNA may provide a substrate for gene activated matrices in gene therapy application in osteoarthritis [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

Synergistic anti-inflammatory and osteogenic n-HA/resveratrol/chitosan composite microspheres for osteoporotic bone regeneration

et al. 2021

Bioactive Materials

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The development of functional materials for osteoporosis is ultimately required for bone remodeling. However, grafts were accompanied by increasing pro-inflammatory cytokines that impaired bone formation. In this work, nano-hydroxyapatite (n-HA)/resveratrol (Res)/chitosan (CS) composite microspheres were designed to create a beneficial microenvironment and help improve the osteogenesis by local sustained release of Res. Study of in vitro release confirmed the feasibility of n-HA/Res/CS microspheres for controlled Res release. Notably, microspheres had anti-inflammatory activity evidenced by the decreased expression of pro-inflammatory cytokines TNF-α, IL-1β and iNOS in RAW264.7 cells in a dose dependent manner. Further, enhanced adhesion and proliferation of BMSCs seeded onto microspheres demonstrated that composite microspheres were conducive to cell growth. The ability to enhance osteo-differentiation was supported by up-regulation of Runx2, ALP, Col-1 and OCN, and substantial mineralization in osteogenic medium. When implanted into bone defects in the osteoporotic rat femoral condyles, enhanced entochondrostosis and bone regeneration suggested that the n-HA/Res/CS composite microspheres were more favorable for impaired fracture healing. The results indicated that optimized n-HA/Res/CS composite microspheres could serve as promising multifunctional fillers for osteoporotic bone defect/fracture treatment.

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“… 252 Introducing BMP-2 plasmid DNA into bone defects can provide a continuous source of growth factors to upregulate bone formation-related genes. 253 VEGF plasmids and NGF plasmids loaded onto 3D-printed porous bone scaffolds can effectively replace seed cells and growth factors, inducing minimal immune response and promoting vascularized bone and nerve regeneration. 254 , 255 The injection of a plasmid encoding fibroblast growth factor 2 (FGF2) around peripheral nerves has also shown potential in facilitating the regeneration of the sciatic nerve.…”

Section: Neuro-bone Tissue Engineeringmentioning

confidence: 99%

Neuro–bone tissue engineering: emerging mechanisms, potential strategies, and current challenges

Sun,

Ye,

Chen

et al. 2023

Bone Res

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The skeleton is a highly innervated organ in which nerve fibers interact with various skeletal cells. Peripheral nerve endings release neurogenic factors and sense skeletal signals, which mediate bone metabolism and skeletal pain. In recent years, bone tissue engineering has increasingly focused on the effects of the nervous system on bone regeneration. Simultaneous regeneration of bone and nerves through the use of materials or by the enhancement of endogenous neurogenic repair signals has been proven to promote functional bone regeneration. Additionally, emerging information on the mechanisms of skeletal interoception and the central nervous system regulation of bone homeostasis provide an opportunity for advancing biomaterials. However, comprehensive reviews of this topic are lacking. Therefore, this review provides an overview of the relationship between nerves and bone regeneration, focusing on tissue engineering applications. We discuss novel regulatory mechanisms and explore innovative approaches based on nerve–bone interactions for bone regeneration. Finally, the challenges and future prospects of this field are briefly discussed.

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BMP-2 plasmid DNA-loaded chitosan films – A new strategy for bone engineering

Cited by 10 publications

References 53 publications

Delivery of the improved BMP-2-Advanced plasmid DNA within a gene-activated scaffold accelerates mesenchymal stem cell osteogenesis and critical size defect repair

Delivery of the improved BMP-2-Advanced plasmid DNA within a gene-activated scaffold accelerates mesenchymal stem cell osteogenesis and critical size defect repair

Synergistic anti-inflammatory and osteogenic n-HA/resveratrol/chitosan composite microspheres for osteoporotic bone regeneration

Neuro–bone tissue engineering: emerging mechanisms, potential strategies, and current challenges

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