Accelerated bony defect healing based on chitosan thermosensitive hydrogel scaffolds embedded with chitosan nanoparticles for the delivery of BMP2 plasmid DNA

Li, Hui; Ji, Qiuxia; Chen, Ximin; Sun, Yan; Xu, Quanchen; Deng, Panpan; Hu, Fang; Yang, Jianjun

doi:10.1002/jbm.a.35900

Cited by 85 publications

(60 citation statements)

References 44 publications

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“…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: 77%

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: 77%

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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“…NPs have been shown to promote the expression of BMP2. 35 Furthermore, NPs have been shown to influence Smad expression 36 and can promote the expression of the Runx2 gene. 37 In addition, recent studies have confirmed that NPs can promote the differentiation of osteoblasts through the BMP2/Smad/Runx2 signaling pathway.…”

Section: Introductionmentioning

confidence: 99%

<p>The Role of Tantalum Nanoparticles in Bone Regeneration Involves the BMP2/Smad4/Runx2 Signaling Pathway</p>

Zhang¹,

Liu²,

Wang³

et al. 2020

IJN

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Background: In recent years, nanomaterials have been increasingly developed and applied in the field of bone tissue engineering. However, there are few studies on the induction of bone regeneration by tantalum nanoparticles (Ta NPs) and no reports on the effects of Ta NPs on the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and the underlying mechanisms. The main purpose of this study was to investigate the effects of Ta NPs on bone regeneration and BMSC osteogenic differentiation and the underlying mechanisms. Materials and Methods: The effects of Ta NPs on bone regeneration were evaluated in an animal experiment, and the effects of Ta NPs on osteogenic differentiation of BMSCs and the underlying mechanisms were evaluated in cell experiments. In the animal experiment, hematoxylin-eosin (HE) staining and hard-tissue section analysis showed that Ta NPs promoted bone regeneration, and immunohistochemistry revealed elevated expression of BMP2 and Smad4 in cells cultured with Ta NPs. Results: The results of the cell experiments showed that Ta NPs promoted BMSC proliferation, alkaline phosphatase (ALP) activity, BMP2 secretion and extracellular matrix (ECM) mineralization, and the expression of related osteogenic genes and proteins (especially BMP2, Smad4 and Runx2) was upregulated under culture with Ta NPs. Smad4 expression, ALP activity, ECM mineralization, and osteogenesis-related gene and protein expression decreased after inhibiting Smad4. Conclusion: These data suggest that Ta NPs have an osteogenic effect and induce bone regeneration by activating the BMP2/Smad4/Runx2 signaling pathway, which in turn causes BMSCs to undergo osteogenic differentiation. This study provides insight into the molecular mechanisms underlying the effects of Ta NPs in bone regeneration.

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“…Beyond technological applications mentioned in this session, hydrogel and nanocomposites based on CS and their derivatives have been studied for other several applications, such as contact lenses [238,239], enzyme and cell separations and immobilizations [71,[240][241][242][243], DNA delivering [244], cartilage and skin regenerations [245][246][247][248][249], biosensors [250][251][252], submucosal fluid or injections [253][254][255][256][257], tissue engineering [258][259][260][261][262][263], postoperative adhesion prevention [264][265][266], cancer treatment [267][268][269][270], orthopedic applications [271,272], artificial muscles [273], and others. Important characteristics of some cited applications are discussed as follows.…”

Section: Other Technological Applicationsmentioning

confidence: 99%

Hydrogels Based on Chitosan and Chitosan Derivatives for Biomedical Applications

Rufato¹,

Galdino²,

Ody³

et al. 2019

Hydrogels - Smart Materials for Biomedical Applications

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Chitosan (CS) is a polymer obtained from chitin, being this, after the cellulose, the most abundant polysaccharide. The fact of (i) CS being obtained from renewable sources; (ii) CS to possess capability for doing interactions with different moieties being such capability dependent of pH; (iii) plenty of possibilities for chemical modification of CS; and (iv) tuning the final properties of CS derivatives makes this polymer very interesting in academic and technological points of view. In this way, hydrogels based on CS and on CS derivatives have been widely used for biomedical applications. Other important technological applications can be also cited, such as adsorbent of metals and dyes in wastewater from industrial effluents. In pharmaceutical field, hydrogels based on CS are often used as drugs' and proteins' carrier formulations due to the inherent characteristics such as the biocompatibility, nontoxicity, hydrophilicity, etc. This chapter is an attempt for updating and joining the plenty of available information regarding the preparation, characterization, and biomedical application of hydrogels based on chitosan and chitosan derivatives. More than 260 references are provided, being the majority of them published in the last 10 years.

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Accelerated bony defect healing based on chitosan thermosensitive hydrogel scaffolds embedded with chitosan nanoparticles for the delivery of BMP2 plasmid DNA

Cited by 85 publications

References 44 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

<p>The Role of Tantalum Nanoparticles in Bone Regeneration Involves the BMP2/Smad4/Runx2 Signaling Pathway</p>

Hydrogels Based on Chitosan and Chitosan Derivatives for Biomedical Applications

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