Strontium-doped Calcium Polyphosphate Scaffold Research Articles

3D Molybdenum Disulfide Nanospheres Loaded with Metformin to Enhance SCPP Scaffolds for Bone Regeneration.

Conventional strontium-doped calcium polyphosphate (SCPP) ceramics have attracted a lot of attention due to good cytocompatibility and controlled degradation. However, their poor mechanical strength, brittleness, and difficulty in eliminating unavoidable postoperative inflammation and bacterial infections in practical applications limit their further clinical application. In this study, carboxylated molybdenum disulfide nanospheres (MoS2-COOH) were first prepared via a one-step hydrothermal method. The optimal doping concentration of MoS2-COOH was then incorporated into SCPP to overcome its poor mechanical strength. To further enhance the anti-inflammatory properties of scaffolds, metformin (MET) was loaded onto MoS2-COOH through covalent bond cross-linking (MoS2-MET). Then MoS2-MET was doped into SCPP (SCPP/MoS2-MET) according to the previously obtained concentration, resulting in the controlled and sustained release of MET from the SCPP/MoS2-MET scaffolds for 21 days in vitro. The SCPP/MoS2-MET scaffolds were shown to have good biological activity in vitro to promote stem cell proliferation and the potential to promote mineralization in vitro. It also showed good osteoimmunomodulatory activity could reduce the expression of proinflammatory factors and effectively induce the differentiation of BMSCs under inflammatory conditions, upregulating the expression of relevant osteoblastic cytokines. In addition, SCPP/MoS2-MET scaffolds could effectively inhibit Staphylococcus aureus and Escherichia coli. In vivo experiments also demonstrated better osteogenic potential of SCPP/MoS2-MET scaffolds compared with the other scaffold-samples. Thus, the introduction of carboxylated molybdenum disulfide nanospheres is a promising approach to improve the properties of SCPP and may provide a new modification strategy for inert ceramic scaffolds and the construction of multifunctional composite scaffolds for bone tissue engineering.

Double-Layer Microsphere Incorporated with Strontium Doped Calcium Polyphosphate Scaffold for Bone Regeneration.

To design and prepare a novel controlled release system for sustained release of two drugs. In this study, a double-layer microsphere was incorporated with strontium-doped calcium polyphosphate (SCPP) scaffold to facilitate bone regeneration and achieve skull repair. The double-layer microsphere combining tetracycline loaded sodium alginate and matrix metalloproteinase-2 (MMP-2) loaded chitosan was manufactured by electrospinning, which were further adhered to SCPP scaffold. The characteristics of microstructure were observed through scanning electron microscope. Loading efficiencies and the optimal ratio of microsphere of the obtained controlled release system were investigated. In addition, the cytotoxicity and the effects on osteoblast proliferation and expressions of osteogenesis-related factors were examined in vitro. Thereafter, the compound material with the controlled release system was implanted in the skull defect of rabbit to evaluate its properties of promoting bone regeneration. The results indicated that this novel controlled release system with SCPP scaffold and the double-layer microspheres loaded with tetracycline and MMP-2 could be a promising material for bones repair.

A promising scaffold with excellent cytocompatibility and pro-angiogenesis action for dental tissue engineering: Strontium-doped calcium polyphosphate.

Angiogenesis is of great importance in dental tissue engineering. Therefore, it is quite necessary for dental tissue engineering to develop a new scaffold with bioactivity to induce angiogenesis. This study was performed to determine the ability of 1% strontium-doped calcium polyphosphate (SCPP) to induce angiogenesis by detecting the levels of VEGF and bFGF from cultured human dental pulp cells (hDPCs). Results of scanning electron microscopy (SEM) and confocal laser scanning microscopy (CLSM) tests indicated the growth of hDPCs on 1%SCPP scaffolds was more superior than that on calcium polyphosphate (CPP) and hydroxyapatite (HA) scaffolds. The detection of MTT indicated 1%SCPP could accelerate proliferation of hDPCs. Further analyzed with ELISA demonstrated the protein levels of VEGF, bFGF from cultured hDPCs on 1%SCPP scaffolds were significantly higher than that on CPP and HA scaffolds. These findings above suggested 1%SCPP could be a promising scaffold for dental tissue engineering to induce angiogenesis.

The co-culture of peripheral blood-derived endothelial progenitor cells and mesenchymal stem cells on three-dimensional porous strontium-doped calcium polyphosphate scaffold for construction of vascularized engineering bone

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Coculture of peripheral blood-derived mesenchymal stem cells and endothelial progenitor cells on strontium-doped calcium polyphosphate scaffolds to generate vascularized engineered bone.

Vascularization of engineered bone tissue is critical for ensuring its survival after implantation and it is the primary factor limiting its clinical use. A promising approach is to prevascularize bone grafts in vitro using endothelial progenitor cells (EPC) derived from peripheral blood. Typically, EPC are added together with mesenchymal stem cells (MSC) that differentiate into osteoblasts. One problem with this approach is how to promote traditional tissue engineering bone survival with a minimally invasive method. In this study, we examined the effectiveness of administering to stimulate the release of peripheral blood stem cells and their co-culturing system for generating prevascularized engineered bone. Cells were isolated by Ficoll density gradient centrifugation and identified as EPC and MSC based on morphology, surface markers, and functional analysis. EPC and MSC were cocultured in several different ratios, and cell morphology and tube formation were assessed by microscopy. Expression of osteogenesis and vascularization markers was quantified by enzyme-linked immunosorbent assay (ELISA), polymerase chain reaction, and histochemical and immunofluorescence staining. Increasing the proportion of EPC in the coculture system led to greater tube formation and greater expression of the endothelial cell marker CD31. An EPC:MSC ratio of 75:25 gave the highest expression of osteogenesis and angiogenesis markers. Cocultures adhered to a three-dimensional scaffold of strontium-doped calcium polyphosphate and proliferated well. Our findings show that coculturing peripheral blood-derived EPC and MSC may prove useful for generating prevascularized bone tissue for clinical use.

Effect of erythromycin‐doped calcium polyphosphate scaffold composite in a mouse pouch infection model

We previously showed that strontium-doped calcium polyphosphate (SCPP) scaffold with poly(vinyl alcohol) (PVA) coating extended the impregnated erythromycin (EM) release. In this study, we examined the bactericidal effect of EM-doped SCPP (SCPP(EM) ) scaffolds with PVA coating in a Staphylococcus aureus (S. aureus) infected mouse pouch. SCPP scaffolds with or without 5% EM, and SCPP(EM) scaffolds coated with PVA (with or without 5% EM) were prepared. Scaffolds were implanted in the pouch of BALB/c mice, followed by inoculation of 1 × 10(3) colony-forming units of S. aureus. Mice were sacrificed 14 days after surgery. Pouch tissues and scaffolds were collected for histology, scanning electron microscopy, and microbiological analysis. In the absence of SCPP scaffolds, the pouch infection was eliminated by the host immune surveillance. In the presence of SCPP scaffolds, both the pouch tissues and scaffolds were infected, but SCPP(EM) scaffolds successfully inhibited bacterial growth. Although PVA coating of SCPP(EM) scaffolds enhanced bacterial growth, incorporation of EM into PVA coating inhibited growth. In conclusion, BALB/c mice were capable of eradicating a low grade S. aureus infection. SCPP protected S. aureus growth from host immune surveillance. Though PVA coating sustained EM release in vitro, it was unable to inhibit bacterial growth because PVA gel matrix provided a temporary shelter for bacteria to grow and slowed the EM release from SCPP scaffold. To guarantee a sufficient inhibition of bacterial growth at the initial stage, embedding EM or other antibiotics in the PVA coating is also essential.

Stimulations of strontium-doped calcium polyphosphate for bone tissue engineering to protein secretion and mRNA expression of the angiogenic growth factors from endothelial cells in vitro

The vascularization of tissue-engineered bone is the key problem needed solving before application of tissue-engineered bone in clinical practice. Meanwhile, endothelial cells are the major and important source of seed cells in bone tissue engineering, and significant on promoting vascularization in tissue-engineered bone. Vascularization (namely angiogenesis) is a process mainly controlled by several angiogenic growth factors (VEGF, bFGF and MMP-2) which can be secreted by endothelial cells. Therefore, the research on the stimulations of SCPP to the secretion of the angiogenic growth factors from endothelial cells is very important. This study was performed to determine the ability of strontium-doped calcium polyphosphate (SCPP) to induce angiogenesis by detecting the protein secretion levels and mRNA expression of VEGF, bFGF and MMP-2 from cultured endothelial cells. As a control, we also researched the effect of HA on the mRNA expressions and protein secretion of angiogenic growth factors from cultured endothelial cells. We cultured endothelial cells with SCPP scaffolds containing various concentration of strontium and HA. The results obtained in the MTT and SEM tests indicated that endothelial cells on SCPP scaffold exhibited higher proliferation rate and were easy to get a good spread than them on CPP, the best state of growth and proliferation of cells could be observed on 8%SCPP. The results of ELISA demonstrated that the protein levels of VEGF, bFGF and MMP-2 from cultured endothelial cells increased with the increasing Sr doped in calcium polyphosphate in SCPP groups, the peaks appeared on 8%SCPP. All SCPP groups showed a better ability to stimulate the protein secretion of VEGF, bFGF and MMP-2 from endothelial cells relative to CPP group and HA group. The results of RT-PCR suggested that the 8%SCPP group exhibited a significantly higher mRNA expression of VEGF, bFGF and MMP-2 relative to CPP group and HA group. In conclusion, the results of this study demonstrated that 8%SCPP had obvious promotion for secretion and mRNA expression of angiogenic growth factors from cultured endothelial cells.

Application of strontium-doped calcium polyphosphate scaffold on angiogenesis for bone tissue engineering

The key factor for regenerating large segmental bone defects through bone tissue engineering is angiogenesis in scaffolds. Attempts to overcome this problem, it is a good strategy to develop a new scaffold with bioactivity to induce angiogenesis in bone tissue engineering. In our previous research, the ability of strontium-doped calcium polyphosphate (SCPP) to stimulate the release of angiogenic growth factors from cultured osteoblasts was studied. This study was performed to determine the ability of SCPP to induce angiogenesis within in vitro co-culture model of human umbilical vein endothelial cells (HUVEC) and osteoblasts co-cultured. The bioactivity of developed scaffolds to induce angiogenesis in vivo was also researched in this paper. Co-cultured model has been developed in vitro and then cultured with SCPP scaffold as well as calcium polyphosphate (CPP) scaffold and hydroxylapatite (HA) scaffold. The results showed that the optimal ratio of HUVEC and osteoblasts co-cultured model for in vitro angiogenesis was 5:1. The model could maintain for more than 35days when cultured with the scaffold and show the best activity at 21st day. Compared with those in CPP and HA scaffold, the formation of tube-like structure and the expression of platelet endothelial cell adhesion molecule in co-cultured model is better in SCPP scaffold. The in vivo immunohistochemistry staining for VEGF also showed that SCPP had a potential to promote the formation of angiogenesis and the regeneration of bone. SCPP scaffold could be served as a potential biomaterial with stimulating angiogenesis in bone tissue engineering and bone repair.

Cell-mediated degradation of strontium-doped calcium polyphosphate scaffold for bone tissue engineering

Bio-ceramic porous scaffolds used in bone tissue engineering are incorporated in vivo by a process of cellular in-growth, followed by cell-mediated degradation and replacement of these scaffolds, in which macrophages and osteoclasts play the key role. Calcium polyphosphate (CPP) is an inorganic polymeric bioceramic which has been increasingly studied as a bone graft. The solution-mediated chemical degradation of strontium-substituted calcium polyphosphate (SCPP) scaffolds is well established in vitro, but an in vitro model of cell-mediated SCPP scaffold degradation has not been investigated. Herein, RAW264.7 (a murine monocyte/macrophage cell line) and osteoclasts were cultured on CPP and SCPP scaffolds. The weight loss and release amount of Sr2+, Ca2+ and PO43− in a degradation medium indicated that macrophages could accelerate the degradation of SCPP. According to the results from MTT assay and scanning electron microscopy, it was found that a low dose of strontium was beneficial to the proliferation of macrophages, while strontium inhibited the activity of osteoclasts. This study will aid in developing SCPP scaffolds for in vivo bone tissue engineering.

Acceleration of segmental bone regeneration in a rabbit model by strontium-doped calcium polyphosphate scaffold through stimulating VEGF and bFGF secretion from osteoblasts

The development of suitable bioactive three-dimensional scaffold for the promotion of bone regeneration is critical in bone tissue engineering. The purpose of this study was to investigate in vivo osteogenesis of the porous strontium-doped calcium polyphosphate (SCPP) scaffolds for bone repair, as well as the relationship between osteogenic properties of SCPP scaffolds and the secretion of bFGF and VEGF from osteoblasts stimulated by SCPP. Besides, the advantages of scaffolds seeded with mesenchymal stem cells (MSCs) for bone repair were also studied. Firstly, the bone repair evaluation of scaffolds was performed on a rabbit segmental bony defects model over a period of 16weeks by histology combined with X-ray microradiography. And then, in order to avoid the influence from the other factors such as hypoxia which emerge in vivo study and affect the secretion of VEGF and bFGF from host cells, human osteoblast-like cells (MG63) were seeded to SCPP, CPP and HA scaffolds in vitro to determine the ability of these scaffolds to stimulate the secretion of angiogenic growth factors (VEGF and bFGF) from MG63 and further explore the reason for the better osteogenic properties of SCPP scaffolds. The histological and X-ray microradiographic results showed that the SCPP scaffolds presented better osteogenic potential than CPP and HA scaffolds, when combined with MSCs, the SCPP scaffolds could further accelerate the bone repair. And the amounts of VEGF measured by ELISA assay in SCPP, CPP and HA groups after cultured for 7days were about 364.989pg/mL, 244.035pg/mL and 232.785pg/mL, respectively. Accordingly, the amounts of bFGF were about 27.085pg/mL, 15.727pg/mL and 8.326pg/mL. The results revealed that the SCPP scaffolds significantly enhanced the bFGF and VEGF secretion compared with other scaffolds. The results presented in vivo and in vitro study demonstrated that the SCPP could accelerate bone formation through stimulating the secretion of VEGF and bFGF from osteoblasts, making it attractive for bone regeneration.

In vitro study in stimulating the secretion of angiogenic growth factors of strontium-doped calcium polyphosphate for bone tissue engineering

Angiogenesis of tissue-engineered bone remains a limited factor for the engineering of larger bone tissue constructs. Attempts to stimulate angiogenesis, using recombinant protein or gene transfer of angiogenic growth factors, have been proposed; however, these approaches have been associated with some problems regarding such as complex technique, expensive prices as well as safety problems and short half-life of angiogenic growth factors. This study was performed to determine the ability of strontium-doped calcium polyphosphate (SCPP) to induce angiogenesis via researching its effect on the mRNA expressions and protein secretion of VEGF and bFGF in/from cultured osteoblasts (ROS17/2.8 cells). We cultured osteoblasts with SCPP scaffolds containing various doses of strontium as well as calcium polyphosphate (CPP) scaffold. Through the detection of MTT and SEM, we have found that SCPP could promote cell proliferation and maintain their morphology. The results of RT-PCR and ELISA indicated that, compared with those in CPP group, the mRNA expression as well as protein levels of VEGF and bFGF in/from cultured osteoblasts were dose-dependent increasing in response to increasing strontium before reaching the peak in SCPP groups, and 8% SCPP showed the optimal promoting role. Therefore, SCPP containing proper dose of strontium could be served as a potential biomaterial with stimulating angiogenesis in bone tissue engineering and bone repair.

In vivo study of porous strontium-doped calcium polyphosphate scaffolds for bone substitute applications

The purpose of this study was to investigate in vivo biocompatibility and osteogenesis as well as degradability of the porous strontium-doped calcium polyphosphate (SCPP) scaffolds as a biomaterial for bone substitute applications. The evaluation was performed on a rabbit model over a period of 16 weeks by histology combined with image analysis, X-ray microradiography and immunohistochemistry methods. The histological and X-ray microradiographic results showed that the SCPP scaffold exhibited good biocompatibility and extensive osteoconductivity with host bone. Moreover, a significant more bone formation was observed in the SCPP group compared with that in the CPP group, especially at the initial stage after implantation. New bone volumes (NBVs) of the SCPP group determined at week 4, 8 and 16 were 14, 27 and 45%, respectively. Accordingly, NBVs of the CPP group were 10, 19 and 40%. Immunohistochemical results revealed that both the expression of collagen type I and bone morphogenetic proteins in the SCPP group were higher than that in the CPP group, which might be associated with the release of strontium ions during the implantation. In addition, during 16 weeks implantation the SCPP scaffold exhibited similar degradability with the CPP scaffold in vivo. Both scaffolds showed the greatest degradation rate for the first 4 weeks, and then the degradation rate gradually decreased. The results presented in this study demonstrated that SCPP scaffold can be considered as a biocompatible material, making it attractive for bone substitute application purposes.

Interaction of endothelial cells with biodegradable strontium-doped calcium polyphosphate for bone tissue engineering

Angiogenesis is of great importance in bone tissue engineering, and has gained large attention in the recent 10 years. However, little research has been done on the effect of biodegradable materials, especially their degradation products on the angiogenesis process. Strontium-doped calcium polyphosphate (SCPP) has been proved to be able to promote osteoblasts growth in vitro before. In the present work, the interaction of endothelial cells (ECs) with the scaffold of SCPP was investigated to evaluate its potential influences on angiogenesis. The cell adhesion on SCPP scaffold as well as the angiogenic behaviors including proliferation, migration and tube-like structure (TLS) formation of ECs treated by its degradation products was tested. The results were compared with those of CPP group and physiological saline (negative control). As the results showed, the surface of SCPP could promote the adhesion and spreading of ECs. Ca 2+ and Pi as well as Sr 2+ were the main degradation products of SCPP. They did not inhibit but could promote the proliferation of ECs within 90 days. Moreover, they could induce the migration and TLS formation of ECs. Since SCPP bears the ability to improve the adhesion and angiogenic behaviors of endothelial cells, it might benefit angiogenesis and serve as a more promising scaffold for bone tissue engineering application. Besides, this work may provide a new method for in vitro evaluation of biodegradable materials’ potential effects on angiogenesis.

In vitro study on the influence of strontium-doped calcium polyphosphate on the angiogenesis-related behaviors of HUVECs

Angiogenesis is of great importance in bone tissue engineering, and has gained large attention in the past decade. Strontium-doped calcium polyphosphate (SCPP) is a novel biodegradable material which has been proved to be able to promote in vivo angiogenesis during bone regeneration. An in vitro culture system was developed in the present work to examine its influence on angiogenesis-related behaviors of human umbilical vein endothelial cells (HUVECs), including cell adhesion, spreading, proliferation and migration. The effects of microtopography, chemical property and the ingredients in the degradation fluid (DF) on cell behaviors were discussed. The results showed that cells attached and spread better on SCPP scaffold than on calcium polyphosphate (CPP), which might partially result from the less rough surface of SCPP scaffold and the less hydrogel formed on the surface. In addition, cell proliferation was significantly improved when treated with SCPP DF compared with the treatment with CPP DF. Statistical analysis indicated that Sr(2+) in SCPP DF might be the main reason for the improved cell proliferation. Moreover, cell migration, another important step during angiogenesis, was evidently stimulated by SCPP DF. The improved in vivo angiogenesis by SCPP might be assigned to its better surface properties and strontium in the DF. This work also provides a new method for in vitro evaluation of biodegradable materials' potential effects on angiogenesis.