Dimethyloxallyl glycine-loaded mesoporous bioactive glass/poly(D,L-lactide) composite scaffolds with ultrasound stimulation for promoting bone repair.

Introduction: Bone tissue engineering is considered the ideal approach for bone repair. Mesoporous bioactive glass (MBG) possesses the characteristics of high drug-loading capacity and bioactivity. Low-intensity pulsed ultrasound contributes to promoting fracture healing and bone defect repair, and dimethyloxalyl glycine (DMOG) is a small molecular inhibitor that can suppress prolyl hydroxylase, reducing the degradation of hypoxia-inducible factor. Methods: In this study, we proposed to prepare DMOG-loaded MBG/poly(D,L-lactide) composite scaffolds (DMOG-MBG/PDLLA) for promoting bone repair. The effects of ultrasound stimulation and DMOG release on the cell responses of rat bone marrow mesenchymal stem cells (BMSCs) and human umbilical vein endothelial cells (HUVECs) and bone repair in vivo were investigated. Results and Discussion: The results showed that both ultrasound stimulation and DMOG release could promote the proliferation, adhesion and differentiation of BMSCs and HUVECs, respectively. After the implantation of scaffolds in rat cranial bone defect model for 8 weeks, the results indicated that the combined ultrasound stimulation and DMOG release contributed to the highest ability for promoting bone repair. Hence, the DMOG-MBG/PDLLA scaffolds with ultrasound stimulation are promising for application in bone repair.

3D Printing of Cobalt-Incorporated Chloroapatite Bioceramic Composite Scaffolds with Antioxidative Activity for Enhanced Osteochondral Regeneration.

Osteochondral defects are often accompanied by excessive reactive oxygen species (ROS) caused by osteoarthritis or acute surgical inflammation. An inflammatory environment containing excess ROS will not only hinder tissue regeneration but also impact the quality of newly formed tissues. Therefore, there is an urgent need to develop scaffolds with both ROS scavenging and osteochondral repair functions to promote and protect osteochondral tissue regeneration. In this work, by using 3D printing technology, a composite scaffold based on cobalt-incorporated chloroapatite (Co-ClAP) bioceramics, which possesses ROS-scavenging activity and can support cell proliferation, adhesion, and differentiation, is developed. Benefiting from the catalytic activity of Co-ClAP bioceramics, the composite scaffold can protect cells from oxidative damage under ROS-excessive conditions, support their directional differentiation, and simultaneously mediate an anti-inflammatory microenvironment. In addition, it is also confirmed by using rabbit osteochondral defect model that the Co-ClAP/poly(lactic-co-glycolic acid) scaffold can effectively promote the integrated regeneration of cartilage and subchondral bone, exhibiting an ideal repair effect in vivo. This study provides a promising strategy for the treatment of defects with excess ROS and inflammatory microenvironments.

Metal-organic frameworks functionalized biomaterials for promoting bone repair.

Bone defects induced by bone trauma, tumors and osteoarthritis greatly affect the life quality and health of patients. The biomaterials with numerous advantages are becoming the most preferred options for repairing bone defects and treating orthopedic diseases. However, their repairing effects remains unsatisfactory, especially in bone defects suffering from tumor, inflammation, and/or bacterial infection. There are several strategies to functionalize biomaterials, but a more general and efficient method is essential for accomplishing the functionalization of biomaterials. Possessing high specific surface, high porosity, controlled degradability and variable composition, metal-organic frameworks (MOFs) materials are inherently advantageous for functionalizing biomaterials, with tremendous improvements having been achieved. This review summarizes recent progresses in MOFs functionalized biomaterials for promoting bone repair and therapeutic effects. In specific, by utilizing various properties of diverse MOFs materials, integrated MOFs functionalized biomaterials achieve enhanced bone regeneration, antibacterial, anti-inflammatory and anti-tumor functions. Finally, the summary and prospects of on the development of MOFs-functionalized biomaterials for promoting bone repair were discussed.

3D-printed gradient scaffolds for osteochondral defects: Current status and perspectives.

Articular osteochondral defects are quite common in clinical practice, and tissue engineering techniques can offer a promising therapeutic option to address this issue.The articular osteochondral unit comprises hyaline cartilage, calcified cartilage zone (CCZ), and subchondral bone.As the interface layer of articular cartilage and bone, the CCZ plays an essentialpart in stress transmission and microenvironmental regulation.Osteochondral scaffolds with the interface structure for defect repair are the future direction of tissue engineering. Three-dimensional (3D) printing has the advantages of speed, precision, and personalized customization, which can satisfy the requirements of irregular geometry, differentiated composition, and multilayered structure of articular osteochondral scaffolds with boundary layer structure. This paper summarizes the anatomy, physiology, pathology, and restoration mechanisms of the articular osteochondral unit, and reviews the necessity for a boundary layer structure in osteochondral tissue engineering scaffolds and the strategy for constructing the scaffolds using 3D printing. In the future, we should not only strengthen the basic research on osteochondral structural units, but also actively explore the application of 3D printing technology in osteochondral tissue engineering. This will enable better functional and structural bionics of the scaffold, which ultimately improve the repair of osteochondral defects caused by various diseases.

Metal-Organic Framework Functionalized Bioceramic Scaffolds with Antioxidative Activity for Enhanced Osteochondral Regeneration.

Osteoarthritis (OA) is a degenerative disease that often causes cartilage lesions and even osteochondral damage. Osteochondral defects induced by OA are accompanied by an inflammatory arthrosis microenvironment with overproduced reactive oxygen species (ROS), resulting in the exacerbation of defects and difficulty regenerating osteochondral tissues. Therefore, it is urgently needed to develop osteochondral scaffolds that can not only promote the integrated regeneration of cartilage and subchondral bone, but also possess ROS-scavenging ability to protect tissues from oxidative stress. Herein, zinc-cobalt bimetallic organic framework (Zn/Co-MOF) functionalized bioceramic scaffolds are designed for repairing osteochondral defects under OA environment. By functionalizing Zn/Co-MOF on the 3D-printed beta-tricalcium phosphate (ß-TCP) scaffolds, the Zn/Co-MOF functionalized ß-TCP (MOF-TCP) scaffolds with broad-spectrum ROS-scavenging ability are successfully developed. Benefiting from its catalytic active sites and degradation products, Zn/Co-MOF endows the scaffolds with excellent antioxidative and anti-inflammatory properties to protect cells from ROS invasion, as well as dual-bioactivities of simultaneously inducing osteogenic and chondrogenic differentiation in vitro. Furthermore, in vivo results confirm that MOF-TCP scaffolds accelerate the integrated regeneration of cartilage and subchondral bone in severe osteochondral defects. This study offers a promising strategy for treating defects induced by OA as well as other inflammatory diseases.

Bioceramic-based scaffolds with antibacterial function for bone tissue engineering: A review.

Bone defects caused by trauma, tumor, congenital abnormality and osteoarthritis, etc. have been substantially impacted the lives and health of human. Artificial bone implants, like bioceramic-based scaffolds, provide significant benefits over biological counterparts and are critical for bone repair and regeneration. However, it is highly probable that bacterial infections occur in the surgical procedures or on bioceramic-based scaffolds. Therefore, it is of great significance to obtain bioceramic-based scaffolds with integrative antibacterial and osteogenic functions for treating bone implant-associated infection and promoting bone repair. To fight against infection problems, bioceramic-based scaffolds with various antibacterial strategies are developed for bone repair and regeneration and also have made great progresses. This review summarizes recent progresses in bioceramic-based scaffolds with antibacterial function, which include drug-induced, ion-mediated, physical-activated and their combined antibacterial strategies according to specific antibacterial mechanism. Finally, the challenges and opportunities of antibacterial bioceramic-based scaffolds are discussed.

Cobalt-doped bioceramic scaffolds fabricated by 3D printing show enhanced osteogenic and angiogenic properties for bone repair.

BACKGROUND: The bone regeneration of artificial bone grafts is still in need of a breakthrough to improve the processes of bone defect repair. Artificial bone grafts should be modified to enable angiogenesis and thus improve osteogenesis. We have previously revealed that crystalline Ca10Li(PO4)7 (CLP) possesses higher compressive strength and better biocompatibility than that of pure beta-tricalcium phosphate (ß-TCP). In this work, we explored the possibility of cobalt (Co), known for mimicking hypoxia, doped into CLP to promote osteogenesis and angiogenesis. METHODS: We designed and manufactured porous scaffolds by doping CLP with various concentrations of Co (0, 0.1, 0.25, 0.5, and 1 mol%) and using 3D printing techniques. The crystal phase, surface morphology, compressive strength, in vitro degradation, and mineralization properties of Co-doped and -undoped CLP scaffolds were investigated. Next, we investigated the biocompatibility and effects of Co-doped and -undoped samples on osteogenic and angiogenic properties in vitro and on bone regeneration in rat cranium defects. RESULTS: With increasing Co-doping level, the compressive strength of Co-doped CLP scaffolds decreased in comparison with that of undoped CLP scaffolds, especially when the Co-doping concentration increased to 1 mol%. Co-doped CLP scaffolds possessed excellent degradation properties compared with those of undoped CLP scaffolds. The (0.1, 0.25, 0.5 mol%) Co-doped CLP scaffolds had mineralization properties similar to those of undoped CLP scaffolds, whereas the 1 mol% Co-doped CLP scaffolds shown no mineralization changes. Furthermore, compared with undoped scaffolds, Co-doped CLP scaffolds possessed excellent biocompatibility and prominent osteogenic and angiogenic properties in vitro, notably when the doping concentration was 0.25 mol%. After 8 weeks of implantation, 0.25 mol% Co-doped scaffolds had markedly enhanced bone regeneration at the defect site compared with that of the undoped scaffold. CONCLUSION: In summary, CLP doped with 0.25 mol% Co2+ ions is a prospective method to enhance osteogenic and angiogenic properties, thus promoting bone regeneration in bone defect repair.

Radiopaque Chitosan Ducts Fabricated by Extrusion-Based 3D Printing to Promote Healing After Pancreaticoenterostomy.

Long-term placement of non-degradable silicone rubber pancreatic duct stents in the body is likely to cause inflammation and injury. Therefore, it is necessary to develop degradable and biocompatible stents to replace silicone rubber tubes as pancreatic duct stents. The purpose of our research was to verify the feasibility and biological safety of extrusion-based 3D printed radiopaque chitosan (CS) ducts for pancreaticojejunostomy. Chitosan-barium sulfate (CS-Ba) ducts with different molecular weights (low-, medium-, and high-molecular weight CS-Ba: LCS-Ba, MCS-Ba, and HCS-Ba, respectively) were soaked in vitro in simulated pancreatic juice (SPJ) (pH 8.0) with or without pancreatin for 16 weeks. Changes in their weight, water absorption rate and mechanical properties were tested regularly. The biocompatibility, degradation and radiopaque performance were verified by in vivo and in vitro experiments. The results showed that CS-Ba ducts prepared by this method had regular compact structures and good molding effects. In addition, the lower the molecular weight of the CS-Ba ducts was, the faster the degradation rate was. Extrusion-based 3D-printed CS-Ba ducts have mechanical properties that match those of soft tissue, good biocompatibility and radioopacity. In vitro studies have also shown that CS-Ba ducts can promote the growth of fibroblasts. These stents have great potential for use in pancreatic duct stent applications in the future.

Analgesia and curative effect of pamidronate disodium combined with chemotherapy on elderly patients with advanced metastatic bone cancer.

The curative effect and adverse reactions of pamidronate disodium in elderly patients with advanced metastatic bone cancer were evaluated. A total of 160 elderly patients with advanced metastatic bone cancer admitted to Affiliated Hospital of Nantong University from February 2012 to January 2015, were divided into the chemotherapy group (n=60) that received routine therapy and the pamidronate disodium group (n=100) that received pamidronate disodium therapy based on the chemotherapy. Pain relief, analgesic time, analgesic duration and side effects were compared between the two groups after treatment. The effect of pain relief in the pamidronate disodium group was significantly higher than that in the chemotherapy group (P<0.001). The total effective rate of the pamidronate disodium group was significantly higher than that of the chemotherapy group (P<0.001). The analgesic onset time in the pamidronate disodium group was earlier than in the chemotherapy group (P<0.001). The analgesic duration in the pamidronate disodium group was longer than that in the chemotherapy group (P<0.001). The incidence of adverse reactions and complications after treatment in the pamidronate disodium group was significantly less than that in the chemotherapy group (P<0.001). The results indicated that pamidronate disodium is effective in the treatment of elderly patients with advanced metastatic bone cancer and patients are less prone to adverse reactions, complications and pain, which is worthy of clinical application.

A novel biopolymer device fabricated by 3D printing for simplifying procedures of pancreaticojejunostomy.

The purpose of our research was to verify the feasibility and effectiveness of a novel three-dimensional printed biopolymer device (3DP-BPD) for duct-to-mucosa pancreaticojejunostomy (PJ) in minipigs. Polylactic acid (PLA) was selected as the raw materials for 3DP-BPD. Three components of a 3DP-BPD were designed and manufactured: hollow stent, supporting disk, and nut. A pancreatic duct dilation model was developed in six minipigs. After 4 weeks, minipigs underwent operations with duct-to-mucosa PJ using 3DP-BPD. The operation time and postoperative complications were analyzed. The anastomotic sites were evaluated grossly 4 weeks and 24 weeks after PJ, and the histological evaluation of anastomotic sites was performed 24 weeks after PJ. The operation time of six stitches duct-to-mucosa PJ was 9.1 ±â€¯1.7 min. All minipigs survived without any adverse events like postoperative pancreatic fistula (POPF). Serum C reactive protein (CRP) and procalcitonin (PCT) levels were normal, and the anastomotic sites were connected tightly on gross observation and touch at 4 weeks and 24 weeks. Histological examinations indicated that the tissues were continuous between the pancreas and the jejunum. The use of 3DP-BPD did not increase the risk of severe local inflammation and POPF. 3DP-BPD used for duct-to-mucosa PJ is more convenient and clinically feasible for pancreatoenteric reconstruction.

The effect of 3 wt.% Cu addition on the microstructure, tribological property and corrosion resistance of CoCrW alloys fabricated by selective laser melting.

Microstructure, tribological property and corrosion resistance of orthopedic implant materials CoCrW-3 wt.% Cu fabricated by selective laser melting (SLM) process were systematically investigated with CoCrW as control. Equaxied γ-phase together with the inside {111} < 112 > type twin and platelet ε-phase was found in both the Cu-bearing and Cu-free alloys. Compared to the Cu-free alloy, the introduction of 3 wt.% Cu significantly increased the volume fraction of the ε-phase. In both alloys, the hardness of ε-phase zone was rather higher (~4 times) than that of γ-phase zone. The wear factor of 3 wt.% Cu-bearing alloy possessed smaller wear factor, although it had higher friction coefficient compared with Cu-free alloys. The ε-phase in the CoCr alloy would account for reducing both abrasive and fatigue wear. Moreover, the Cu-bearing alloy presented relatively higher corrosion potential Ecorr and lower corrosion current density Icorr compared to the Cu-free alloy. Accordingly, 3 wt.% Cu addition plays a key role in enhancing the wear resistance and corrosion resistance of CoCrW alloys, which indicates that the SLM CoCrW-3Cu alloy is a promising personalized alternative for traditional biomedical implant materials.

Preliminary study on the corrosion resistance, antibacterial activity and cytotoxicity of selective-laser-melted Ti6Al4V-xCu alloys.

In this study, a series of Cu-bearing Ti6Al4V-xCu (x=0, 2, 4, 6wt%) alloys (shorten by Ti6Al4V, 2C, 4C, and 6C, respectively.) with antibacterial function were successfully fabricated by selective laser melting (SLM) technology with mixed spherical powders of Cu and Ti6Al4V for the first time. In order to systematically investigate the effects of Cu content on the microstructure, phase constitution, corrosion resistance, antibacterial properties and cytotoxicity of SLMed Ti6Al4V-xCu alloys, experiments including XRD, SEM-EDS, electrochemical measurements, antibacterial tests and cytotoxicity tests were conducted with comparison to SLMed Ti6Al4V alloy (Ti6Al4V). Microstructural observations revealed that Cu had completely fused into the Ti6Al4V alloy, and presented in the form of Ti2Cu phase at ambient temperature. With Cu content increase, the density of the alloy gradually decreased, and micropores were obviously found in the alloy. Electrochemical measurements showed that corrosion resistance of Cu-bearing alloys were stronger than Cu-free alloy. Antibacterial tests demonstrated that 4C and 6C alloys presented strong and stable antibacterial property against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) compared to the Ti6Al4V and 2C alloy. In addition, similar to the Ti6Al4V alloy, the Cu-bearing alloys also exerted good cytocompatibility to the Bone Marrow Stromal Cells (BMSCs) from Sprague Dawley (SD) rats. Based on those results, the preliminary study verified that it was feasible to fabricated antibacterial Ti6Al4V-xCu alloys direct by SLM processing mixed commercial Ti6Al4V and Cu powder.

Preliminary assessment of metal-porcelain bonding strength of CoCrW alloy after 3wt.% Cu addition.

In this work, a novel Cu-bearing CoCrW alloy fabricated by selective laser melting for dental application has been studied. For its successful application, the bonding strength of metal-porcelain is essential to be systematically investigated. Therefore, the aim of this study was to evaluate the metal-porcelain bonding strength of CoCrWCu alloy by three-point bending test, meanwhile the Ni-free CoCrW alloy was used as control. The oxygen content was investigated by an elemental analyzer; X-ray photoelectron spectroscopy (XPS) was used to analyze the surface chemical composition of CoCrW based alloy after preoxidation treatment; the fracture mode was investigated by X-ray energy spectrum analysis (EDS) and scanning electron microscope (SEM). Result from the oxygen content analysis showed that the content of oxygen dramatically increased after the Cu addition. And the XPS suggested that Co-oxidation, Cr2O3, CrO2, WO3, Cu2O and CuO existed on the preoxidated surface of the CoCrWCu alloy; the three-point bending test showed that the bonding strength of the CoCrWCu alloy was 43.32 MPa, which was lower than that of the CoCrW group of 47.65 MPa. However, the average metal-porcelain bonding strength is significantly higher than the minimum value in the ISO 9693 standard. Results from the SEM images and EDS indicated that the fracture mode of CoCrWCu-porcelain was mixed between cohesive and adhesive. Based on the results obtained in this study, it can be indicated that the Cu-bearing CoCrW alloy fabricated by the selective laser melting is a promising candidate for use in dental application.

Investigation on the microstructure, mechanical property and corrosion behavior of the selective laser melted CoCrW alloy for dental application.

In this study, an experimental investigation on fabricating Ni-free CoCrW alloys by selective laser melting (SLM) for dental application was conducted in terms of microstructure, hardness, mechanical property, electrochemical behavior, and metal release; and line and island scanning strategy were applied to determine whether these strategies are able to obtain expected CoCrW parts. The XRD revealed that the γ-phase and ε-phase coexisted in the as-SLM CoCrW alloys; The OM and SEM images showed that the microstructure of CoCrW alloys appeared square-like pattern with the fine cellular dendrites at the borders; tensile test suggested that the difference of mechanical properties of line- and island-formed specimens was very small; whilst the outcomes from the electrochemical and metal release tests indicated that the island-formed alloys showed slightly better corrosion resistance than line-formed ones in PBS and Hanks solutions. Considering that the mechanical properties and corrosion resistance of line-formed and island-formed specimens meet the standards of ISO 22674:2006 and EN ISO 10271, CoCrW dental alloys can be successfully fabricated by line and island scanning strategies in the SLM process.

Cyclopamine is a novel Hedgehog signaling inhibitor with significant anti-proliferative, anti-invasive and anti-estrogenic potency in human breast cancer cells.

Stimulation of Hedgehog (Hh) signaling induces carcinogenesis or promotes cell survival in cancers of multiple organs. In epithelial cancer with aberrant Hedgehog activation, abrogation of Hedgehog signaling by cyclopamine, a naturally occurring Hedgehog-specific small-molecule inhibitor, causes profound inhibition of tumor growth. In the present study, cyclopamine displayed a significant potency in suppressing the proliferation of both estrogen-responsive (MCF-7) and estrogen-independent (MDA-MB-231) human breast cancer cells. Cyclopamine induced a robust G1 cell cycle arrest and elicited notable effects on the expression of cyclin D1 through modulation of the MAPK/ERK signaling pathway. Cyclopamine also inhibited the invasive ability of both breast cancer cell lines by suppressing the expression levels of NF-κB, MMP2 and MMP9 protein. Furthermore, in estrogen-responsive MCF-7 cells, cyclopamine significantly downregulated the production of estrogen receptor-α protein. Our results implicate cyclopamine as a novel, potent inhibitor of human breast cancer proliferation and estrogen responsiveness that could potentially be developed into a promising therapeutic agent for the treatment of breast cancer.