A pH-Responsive Cluster Metal-Organic Framework Nanoparticle for Enhanced Tumor Accumulation and Antitumor Effect.

As a result of the deficient tumor-specific antigens, potential off-target effect, and influence of protein corona, metal-organic framework nanoparticles have inadequate accumulation in tumor tissues, limiting their therapeutic effects. In this work, a pH-responsive linker (L) is prepared by covalently modifying oleylamine (OA) with 3-(bromomethyl)-4-methyl-2,5-furandione (MMfu) and poly(ethylene glycol) (PEG). Then, the L is embedded into a solid lipid nanoshell to coat apilimod (Ap)-loaded zeolitic imidazolate framework (Ap-ZIF) to form Ap-ZIF@SLN#L. Under the tumor microenvironment, the hydrophilic PEG and MMfu are removed, exposing the hydrophobic OA on Ap-ZIF@SLN#L, increasing their uptake in cancer cells and accumulation in the tumor. The ZIF@SLN#L nanoparticle induces reactive oxygen species (ROS). Ap released from Ap-ZIF@SLN#L significantly promotes intracellular ROS and lactate dehydrogenase generation. Ap-ZIF@SLN#L inhibits tumor growth, increases the survival rate in mice, activates the tumor microenvironment, and improves the infiltration of macrophages and T cells in the tumor, as demonstrated in two different tumor-bearing mice after injections with Ap-ZIF@SLN#TL. Furthermore, mice show normal tissue structure of the main organs and the normal serum level in alanine aminotransferase and aspartate aminotransferase after treatment with the nanoparticles. Overall, this pH-responsive targeting strategy improves nanoparticle accumulation in tumors with enhanced therapeutic effects.

Osteogenic and anti-tumor Cu and Mn-doped borosilicate nanoparticles for syncretic bone repair and chemodynamic therapy in bone tumor treatment.

Critical bone defects caused by extensive excision of malignant bone tumor and the probability of tumor recurrence due to residual tumor cells make malignant bone tumor treatment a major clinical challenge. The present therapeutic strategy concentrates on implanting bone substitutes for defect filling but suffers from failures in both enhancing bone regeneration and inhibiting the growth of tumor cells. Herein, Cu and Mn-doped borosilicate nanoparticles (BSNs) were developed for syncretic bone repairing and anti-tumor treatment, which can enhance bone regeneration through the osteogenic effects of Cu2+ and Mn3+ ions and meanwhile induce tumor cells apoptosis through the hydroxyl radicals produced by the Fenton-like reactions of Cu2+ and Mn3+ ions. In vitro study showed that both osteogenic differentiation of BMSCs and angiogenesis of endothelial cells were promoted by BSNs, and consistently the critical bone defects of rats were efficiently repaired by BSNs through in vivo evaluation. Meanwhile, BSNs could generate hydroxyl radicals through Fenton-like reactions in the simulated tumor microenvironment, promote the generation of intracellular reactive oxygen species, and eventually induce tumor cell apoptosis. Besides, subcutaneous tumors of mice were effectively inhibited by BSNs without causing toxic side effects to normal tissues and organs. Altogether, Cu and Mn-doped BSNs developed in this work performed dual functions of enhancing osteogenesis and angiogenesis for bone regeneration, and inhibiting tumor growth for chemodynamic therapy, thus holding a great potential for syncretic bone repairing and anti-tumor therapy.

In Situ Photo-Cross-Linking Hydrogel Accelerates Diabetic Wound Healing through Restored Hypoxia-Inducible Factor 1-Alpha Pathway and Regulated Inflammation.

The hypoxia-inducible factor 1-alpha (HIF-1a) pathway plays a key role in regulating angiogenesis during wound healing. However, the diabetic condition hampers the stabilization of HIF-1a and thus inhibits the subsequent angiogenesis, and meanwhile, the function and phenotype transition of macrophage are impaired in the diabetic condition, which leads to prolonged and chronic inflammation. Both angiogenesis inhibition and inflammatory dysfunction make diabetic wound healing a major clinical challenge. Here, borosilicate (BS), a new group of bioceramics with a coupled network of interconnected [BO3] and [SiO4] which can incorporate therapeutic ions such as Cu2+, is synthesized and combined with silk fibroin (SF), a biocompatible natural amino acid polymer whose composition and structure are similar to a natural extracellular matrix (ECM), to obtain a compound system which can transform into a SF-MA-BS hydrogel under UV radiation via methacryloyloxy (MA) groups modified on both BS and SF. When in use, the compound system can thoroughly spread to the whole wound surface and be in situ photo-cross-linked to form an integral SF-MA-BS hydrogel that firmly adheres to the wound, protects the wound from external contamination, and further spontaneously promotes wound regeneration by releasing therapeutic ions. The wound repair of Streptozotocin-induced diabetic rats shows that diabetic wound healing is obviously accelerated by SF-MA-BS, interestingly the HIF-1a pathway is restored via interaction between HIF-1a and Cu2+, and angiogenesis is therefore enhanced. Meanwhile, inflammation is well regulated by SF-MA-BS, and long-term detrimental inflammation is avoided. These findings indicate that the SF-MA-BS hydrogel regenerates diabetic wounds, and further clinical trials are anticipated.

A novel 3D printed bioactive scaffolds with enhanced osteogenic inspired by ancient Chinese medicine HYSA for bone repair.

Some traditional Chinese medicine (TCM) has been applied in bone repair, however, hydroxy-safflower yellow A (HYSA), one composition of safflower of the typical invigorating the circulation of TCM, has little been studied in orthopedics field for osteogenesis and angiogenesis clinically. Herein, we hypothetically speculated that the synthetic bioactive glasses (BG, 1393) scaffolds carried HYSA by a 3D print technique could enhance osteogenic repair properties. Notably, scaffolds coating chitosan/sodium alginate endowed with excellent drug control release ability, and significantly improved the BG mechanical strength. HYSA was loaded into BG scaffolds by coating chitosan/sodium alginate film, and the osteogenesis and angiogenesis of the HYSA/scaffolds were evaluated in vitro and in vivo. In vitro the cell culture results exhibited that the high dose of HYSA (0.5 mg/ml) loaded scaffolds can promote the proliferation of bone marrow stromal cells (rBMSCs) and migration, tubule formation of human umbilical vein endothelial cells (HUVECs). The active alkaline phosphatase (ALP) of rBMSCs can also be improved by the high dose of HYSA/scaffolds. Results of qRT-PCR and Western blot indicated that the high dose of HYSA/scaffolds can up-regulate ALP, OCN, OPN and RUNX-2 expression and relative protein secretion of the HIF-1α and BMP-2. In the animal experiment, the high dose of HYSA/scaffolds has a significantly better capacity to promote new bone formation than the undoped scaffolds at 8 weeks post-surgery. Thus, our results claimed that the novel HYSA/scaffolds hold the substantial potential to be further developed as effective and safe bone tissue engineering biomaterials for bone regeneration by combining enhanced osteogenesis and angiogenesis.

Chemically and physically cross-linked polyvinyl alcohol-borosilicate gel hybrid scaffolds for bone regeneration.

The composite scaffolds of bioactive glasses and polymers are often used in bone regeneration which could improve the stiffness, compressive strength and bioactivity of polymers while maintaining the osteoconductivity and osteoinductivity of bioactive glasses. But due to complicated situations and limitations of compositing process, the prepared composite materials have low uniformity and obvious phase separation, leading to problems such as poor mechanical properties and inferior new bone formation capacity. In this paper, a modified sol-gel processing technique was used to realize the homogeneous inorganic-organic composites. After hydrolysis of the metal alkoxide, the sol was mixed with the aqueous solution of polyvinyl alcohol (PVA), and through gelation and chemical reaction, the mixture was solidified into the inorganic-organic composite hydrogel. The composites showed as a uniform single phase with interpenetrating networks of PVA gel and borosilicate gel (BG) that chemically and physically interacted at the scale of molecular or nanometer, therefore PVA-BG hybrids were obtained. When immersed in phosphate-buffered saline, the PVA-BG hybrid-derived scaffolds released beneficial ions into the medium and converted to hydroxyapatite. The scaffolds were not toxic to the rat bone marrow-derived mesenchymal stem cells (rBMSCs), and supported rBMSCs proliferation. Furthermore, the alkaline phosphatase activity of the rBMSCs and the expression levels of osteogenic-related genes (alkaline phosphatase, osteocalcin and runt-related transcription factor 2) increased significantly with increasing amount of BG in the hybrid scaffolds. Finally, the bone defect repair results of critical-sized femoral condyle defect rat model demonstrated that PVA-BG hybrid scaffolds could enhance bone regeneration compared with PVA scaffolds. The results suggested that PVA-BG hybrid scaffolds may be a promising biomaterial for bone regeneration.

Angiogenesis and Full-Thickness Wound Healing Efficiency of a Copper-Doped Borate Bioactive Glass/Poly(lactic- co-glycolic acid) Dressing Loaded with Vitamin E in Vivo and in Vitro.

There is an urgent demand for wound healing biomaterials because of the increasing frequency of traffic accidents, industrial contingencies, and natural disasters. Borate bioactive glass has potential applications in bone tissue engineering and wound healing; however, its uncontrolled release runs a high risk of rapid degradation and transient biotoxicity. In this study, a novel organic-inorganic dressing of copper-doped borate bioactive glass/poly(lactic- co-glycolic acid) loaded with vitamin E (0-3.0 wt % vitamin E) was fabricated to evaluate its efficiency for angiogenesis in cells and full-thickness skin wounds healing in rodents. In vitro results showed the dressing was an ideal interface for the organic-inorganic mixture and a controlled release system for Cu2+ and vitamin E. Cell culture suggested the ionic dissolution product of the copper-doped and vitamin E-loaded dressing showed the best migration, tubule formation, and vascular endothelial growth factor (VEGF) secretion in human umbilical vein endothelial cells (HUVECs) and higher expression levels of angiogenesis-related genes in fibroblasts in vitro. Furthermore, this dressing also suggested a significant improvement in the epithelialization of wound closure and an obvious enhancement in vessel sprouting and collagen remodeling in vivo. These results indicate that the copper-doped borate bioactive glass/poly(lactic- co-glycolic acid) dressing loaded with vitamin E is effective in stimulating angiogenesis and healing full-thickness skin defects and is a promising wound dressing in the reconstruction of full-thickness skin injury.

Mesoporous bioactive glass-coated 3D printed borosilicate bioactive glass scaffolds for improving repair of bone defects.

Background: In the field of tissue engineering, there is currently increasing interest in new biomedical materials with high osteogenic ability and comparable mechanical function to repair bone defects. Three-dimensional (3-D) bioactive borosilicate glass (BG) scaffolds exhibit uniform interconnected macro-pores, high porosity and high compressive strength. In this study, we fabricated 3-D BG scaffolds by the 3D printing technique, then coated the surface of the 3-D BG scaffolds with mesoporous bioactive glass (MBG) (BG-MBG scaffold). Methods: The biocompatibility of the BG-MBG scaffolds was evaluated by assessing biodegradability, cell proliferation, alkaline phosphatase (ALP) activity and by quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis of osteogenic gene expression with human bone marrow stromal cells (hBMSCs). Moreover, the BG-MBG scaffolds were used to repair rat femoral defects and their performance was evaluated using microcomputed tomography (micro-CT), fluorescence labeling, histological analysis and immunohistochemical (IHC) analysis. Results: The results showed that the BG-MBG scaffolds possessed ordered nearly 4nm meso-pores and regular macro-pores, as well as good biodegradability, and that they stimulated the proliferation and osteogenic differentiation of hBMSCs. In in vivo studies, the result of micro-CT reconstructed images (BG-9M group, 0.63 ± 0.02 g/cm3 and BG group 0.13 ± 0.02 g/cm3 ) and van Gieson staining (BG-9M groups, 62.67 ± 3.39% and BG group, 12.33 ± 2.58%) showed that the BG-MBG scaffolds could significantly enhance new bone formation in both inner and peripheral scaffolds in defects, in and in without the presence of growth factors or stem cells (P < 0.05). Conclusions: It is believed from these results that the BG-MBG scaffolds possess excellent osteoinductive and osteogenic properties which will make them appealing candidates for bone defect repair. The novelty of our research is to provide a new material to treat bone defects in clinic.

[Study of spectra characteristics of Dy3+ -activated LiSrBO3 phosphor].

The LiSrBO3:Dy3+ phosphor was synthesized by solid-state method. SrCO2 (99.9%), Li2CO3 (99.9%), H3BO3 (99.9%) and Dy2O3 (99.9%) were used as starting materials. After these individual materials were blended and grounded thoroughly in an agate mortar, the homogeneous mixture was heated at 700 degrees C for 2 h in air, and LiSrBO3:Dy3+ phosphors were obtained. The phase present of the samples was characterized by powder X-ray diffraction (XRD) (D/max-rA, Cu Kalpha, 40 kV, 40 mA, lamda = 0.15406 nm). The excitation and emission spectra of these phosphors were measured by a RF-540 photoluminescence spectrophotometer. The emission spectrum of LiSrBO3:Dy3+ phosphor shows several bands at 486, 578 and 668 nm, respectively. The excitation spectrum for 578 nm emission has several excitation bands at 331, 368, 397, 433, 462 and 478 nm, respectively. The effect of Dy3+ concentration on the emission intensity of LiSrBO3:Dy3+ was investigated, and the result shows that the emission intensity of LiSrBO3:Dy3+ phosphor firstly increases with increasing Dy2+ concentration, then decreases, viz. the concentration quenching exists. And the Dy3+ concentration corresponding to the maximal emission intensity is 3 mol%, and the concentration quenching mechanisms are the d-d interaction by Dexter theory.