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Regeneration of osteochondral tissue is of great potentialities in repairing severe osteochondral defects. However, anisotropic physiological characteristics and tissue linage difference make the regeneration of osteochondral tissue remain a huge challenge. Herein, a multicellular system based on a bilayered co-culture scaffold mimicking osteochondral tissues was successfully developed for an alternative of osteochondral regeneration via a 3D bioprinting strategy. The dual function of integrally repairing both cartilage and bone could be achieved by designing multiple-cells distribution and a cell-induced bioink containing bioceramic particles. As an important bioactive agent, the Li-Mg-Si bioceramics-containing bioink exhibited the function of simultaneously stimulating multiple cells for differentiation towards specific directions. The 3D bioprinted co-culture scaffolds showed the capacity for osteochondral tissue regeneration by inducing osteogenic and chondrogenic differentiation in vitro and accelerating the repair of severe osteochondral defects in vivo. This study offers a potential strategy for complex tissue reconstruction through bioprinting multiple tissue cells in combination of bioceramics-stimulating bioinks.

The deep burn skin injures usually severely damage the dermis with the loss of hair follicle loss, which are difficult to regenerate. Furthermore, severe burns often accompanied with large amount of wound exudates making the wound moist, easily infected, and difficult to heal. Therefore, it is of great clinical significance to develop wound dressings to remove wound exudates and promote hair follicle regeneration. In this study, a sandwich-structured wound dressing (SWD) with Janus membrane property was fabricated by hot compression molding using hydrophilic zinc silicate bioceramics (Hardystonite, ZnCS) and hydrophobic polylactic acid (PLA). This unique organic/inorganic Janus membrane structure revealed excellent exudate absorption property and effectively created a dry wound environment. Meanwhile, the incorporation of ZnCS bioceramic particles endowed the dressing with the bioactivity to promote hair follicle regeneration and wound healing through the release of Zn2+ and SiO32− ions, and this bioactivity of the wound dressing is mainly attributed to the synergistic effect of Zn2+ and SiO32− to promote the recruitment, viability, and differentiation of hair follicle cells. Our study demonstrates that the utilization of the Janus membrane and synergistic effect of different type bioactive ions are effective approaches for the design of wound dressings for burn wound healing., Graphical abstract Image 1, Highlights • A sandwich-structured wound dressing is constructed using ZnCS ceramic powder and PLA fiber membrane (ZnCS-SWD). • ZnCS-SWD has Janus membrane property to absorb wound exudate unidirectionally from wound bed to the dressing. • The combination of Zn2+ and SiO32- ions is found to have a synergistic effect to promote burn wound healing.

Although calcium phosphate cements (CPCs) have been clinically used to repair bone defects caused by bone tumor resection, traditional CPCs cannot kill the remaining tumor cells after surgery and prevent cancer recurrence. In this study, a multifunctional injectable metal-organic framework (MOF) cobalt coordinated tetrakis(4-carboxyphenyl)porphyrin (Co-TCPP)-modified calcium phosphate cement (Co-TCPP/CPC) was prepared for the minimally invasive treatment of neoplastic bone defects. The incorporation of Co-TCPP not only retained the good injectability of bone cements, but also shortened the setting time, improved the compressive strength, and endowed them with excellent photothermal properties. The hyperthermia effect induced by the presence of Co-TCPP well induced the therapeutic effect against bone tumors both in vitro and in vivo. Moreover, Co-TCPP/CPC exhibited desirable osteogenesis and angiogenesis by promoting bone and vascular regeneration in vivo. Therefore, the Co-TCPP composite bone cement demonstrated its great potential for bone tumor therapy and tissue regeneration, representing a multifunctional biomaterial for the treatment of neoplastic bone defects.

Titanium alloy scaffolds have recently gained substantial interest for the treatment of critical-size bone defect, particularly along with the maturity of the 3D printing technology that is capable of turning scaffold design ideas into real implants. As titanium alloys lack surface osteogenic activity, for improved biological performance of such scaffolds, surface modification is necessary. Various coating materials and coating methods have been explored. In this study, we developed a unique surface modification method to provide the surface of 3D printed titanium scaffolds with nano-sized structure and bioactive agent. Uniform, ordered TiO2 nanotube arrays were formed by applying two-step anodization, and then mesoporous bioactive glass (MBG) was loaded into nanotubes. The results of in vitro immersion testing showed that bioactive ions, i.e., Si and Ca ions, could be steadily and continuously released from MBG into basal medium. The assessment of the responses of hBMSCs confirmed that the surface-modified scaffolds supported the adhesion and proliferation of hBMSCs, indicating good surface cytocompatibility. The developed method of combining surface nanostructure and bioactive agent could be used as a new strategy to improve the osteogenic activity of 3D printed titanium alloy scaffolds.

In deep burn injuries, the dermis of the skin is often severely damaged, and hair follicles are also lost and lose the potential for regeneration. Therefore, the development of wound dressings that promote hair follicle regeneration has important clinical significance. In this study, inspired by an ancient Chinese medicine prescription, a novel fibrous membrane (P/Qu/Cup; P, PCL; Qu, quercetin; Cup, cuprorivaite, CaCuSi4O10) containing quercetin-copper (Qu-Cu) chelates was fabricated by using quercetin and a highly bioactive bioceramic (CaCuSi4O10) incorporated in PCL/gelatin electrospun fibers. The fibrous membrane can effectively release Qu and Cu ions to induce proliferation, migration, and differentiation of skin and hair follicle related cells, and the Qu, Cu ions, and Si ions released from the composite membrane revealed synergistic activity to stimulate hair follicle regeneration and wound healing. Our study demonstrated that the analysis of the common components in ancient Chinese prescription is an effective approach to design novel bioactive materials for regenerative medicine.

The immunomodulatory capability of biomaterials is of paramount importance for successful material-mediated bone regeneration. Particularly, the design of surface nano-topography can be leveraged to instruct immune reactions, yet the understanding of such "nano-morphology effect" is still very limited. Herein, highly ordered nano-concave pit (denoted as NCPit) and nano-convex dot (denoted as NCDot) microarrays with two different sizes were successfully constructed on a 316LSS surface via anodization and subsequently immersion-coating treatment, respectively. We, for the first time, comparatively investigated the interactions of NCPit and NCDot microarrays with RAW264.7 macrophages and their immunomodulatory impacts on osteogenesis and angiogenesis of human bone mesenchymal stem cells (hBMSCs) and human umbilical vein endothelial cells (HUVECs). NCDot microarrays induced macrophages towards M2 polarization with the higher expression level of anti-inflammatory markers (IL-10 and CD 206) and the lower level of pro-inflammatory markers (TNF-α, IL-1β, IL-6 and CD 86) than those of the corresponding NCPit microarrays. During the process, the expressions of osteogenesis-related genes (Runx2, OPN and OCN) of hBMSCs, and angiogenesis-related genes (eNOS, HIF-1α, KDR and VEGF) of HUVECs were significantly upregulated by the NCDot microarray-modulating immune microenvironment of macrophages, and finally stimulated osteogenesis and angiogenesis. Thus, the prepared NCDot arrays were able to significantly promote osteo-/angiogenic activity by generating a more suitable immune microenvironment than NCPit arrays, offering substantial evidence for designing immunomodulatory biomaterials with specific microstructures and optimal bioactivity.

Bioceramics are widely used in bone tissue repair and regeneration due to their desirable biocompatibility and bioactivity. However, the brittleness of bioceramics results in difficulty of surgical operation, which greatly limits their clinical applications. The spicules of the marine sponge Euplectella aspergillum (Ea) possess high flexibility and fracture toughness resulting from concentric layered silica glued by a thin organic layer. Inspired by the unique properties of sponge spicules, flexible bioceramic-based scaffolds with spicule-like concentric layered biomimetic microstructures were constructed by combining two-dimensional (2D) bioceramics and 3D printing. 2D bioceramics could be assembled and aligned by modulating the shear force field in the direct ink writing (DIW) of 3D printing. The prepared spicules-inspired flexible bioceramic-based (SFB) scaffolds differentiated themselves from traditional 3D-printed irregular particles-based bioceramic-based scaffolds as they could be adaptably compressed, cut, folded, rolled and twisted without the occurrence of fracture, significantly breaking through the bottleneck of inherent brittleness of traditional bioceramic scaffolds. In addition, SFB scaffolds showed significantly enhanced in vitro and in vivo bone-forming bioactivity as compared to conventional β-tricalcium phosphate (β-TCP) scaffolds, suggesting that SFB scaffolds combined both of excellent mechanical and bioactive characteristics, which is believed to greatly promote the bioceramic science and their clinical applications.

For the postoperative treatment of bone cancer, biomaterials should possess an antitumor effect and simultaneous repair ability of bone defects. Compared with single photothermal treatment or magnetothermal treatment, photo/magnetothermal joint treatment represents a more high-efficient strategy to kill tumor cells. In this work, a 3D-printed bioceramic scaffold with a photo/magnetothermal effect was successfully designed and fabricated, which exhibited the function of killing tumor cells and excellent osteogenic bioactivity, via incorporating an Fe element into akermanite (AKT) bioceramics. After doping with ferric elements, the AKT scaffolds possessed significantly enhanced compressive strength and desirable ferromagnetic property. The ferric elements endowed the AKT scaffolds with excellent photo/magnetothermal effects, and hence the scaffolds could efficiently kill tumor cells in vitro under mild laser power density and magnetic field. In addition, the Fe-doped AKT bioceramic scaffolds significantly promoted cell proliferation and osteogenic differentiation of rabbit bone mesenchymal stem cells as compared with the original AKT scaffolds without Fe elements. The results suggest that Fe-doped bioceramic scaffolds with both photo/magnetothermal effect and in vitro osteogenic bioactivity could be a promising biomaterial for the synergistic therapy of bone cancers.

Bone tumors may lead to osteoporosis. It is of great significance to fabricate functional scaffolds for treating bone tumor, osteoporosis and repairing bone defects. In this study, LaB6 micro-nanoparticles/poly( d , l -lactide)-modified β-tricalcium phosphate scaffolds (TCP-PDLLA-LB) were successfully prepared. The LaB6 surface chemistry-reinforced TCP-PDLLA-LB scaffolds were endowed with the following excellent properties: (1) the enhanced mechanical strength. The TCP-PDLLA-5LB scaffolds possessed higher compression resistant capacity than TCP scaffolds owing to the strong adhesive property of PDLLA that bound the LaB6 micro-nanoparticles and scaffolds tightly; (2) the excellent photothermal performance. TCP-PDLLA-LB scaffolds presented distinct photothermal property because of localized surface plasmon resonance effect of LaB6 micro-nanoparticles when exposed to the near-infrared (NIR) light (wavelength: 808 nm) and it was flexibly controllable through changing the quantity of LaB6 micro-nanoparticles, power density of NIR light and environmental humidity; (3) the excellent biological properties in vitro. When culturing with saos-2 bone tumor cells, the TCP-PDLLA-5LB scaffolds effectively killed the saos-2 cells through adjusting power density of NIR light, irradiation duration time of NIR light and irradiation times of NIR light. Additionally, the TCP-PDLLA-5LB scaffolds were able to release bioactive ions which were beneficial to the in vitro osteogenesis of rabbit bone marrow stromal cells (rBMSCs) by supporting the attachment and proliferation of rBMSCs as well as promoting the expressions of osteogenic genes BMP2, RUNX2 and COL 1; and (4) the abilities of effectively ablating bone tumors and supporting bone tissue regeneration in vivo. The bone tumor tissues were significantly ablated and suppressed through hyperthermia due to the existence of LaB6 micro-nanoparticles on the scaffolds. Simultaneously, TCP-PDLLA-5LB scaffolds implanted in bone defects effectively helped new bone formation regardless of NIR light irradiation. In conclusion, LaB6 surface chemistry-reinforced scaffolds possess the dual functions of ablating bone tumor and repairing bone defects, which offers a promising therapy strategy for tumor/disease-related bone tissue engineering.

Although the akermanite (Ca2MgSi2O7) bioceramic has been confirmed to possess favorable osteogenic activity, until now little was known about its in vivo subchronic systemic toxicity, which is important for determining the biocompatibility and the clinical applications of the material in bone implants. In this study, the subchronic systemic toxicity of akermanite bioceramic was for the first time investigated according to well-accepted ISO standard methods. Following the method, healthy adult Wistar rats were injected with certain amounts of extracts of akermanite bioceramic that was intended to simulate the ionic product during the degradation of the material when implanted into the body. At day 28 after injection, the general body conditions, blood cytology, blood biochemistry and histology of all important organs of the rats were examined. The results showed that there was no significant difference in the hemoglobin concentration, red blood cell count, platelet count and white blood cell count between the rats with injection of akermanite bioceramic extracts and the saline control. The indicators of liver function, including aspartate aminotransferase and alkaline phosphatase, and kidney function, including blood urea nitrogen and creatinine, did not show significant difference between the two groups (P > 0.05). In addition, the results of histological examination showed that the extract of akermanite bioceramic did not cause any pathological changes to important organs such as the heart, liver and kidneys. These findings demonstrated that the ionic product derived from the degradation of akermanite bioceramic did not cause in vivo subchronic systemic toxicity. The results of the current study provided more strengthened evidence for the biosafety of akermanite bioceramic and suggest that this material with desirable biocompatibility may be a potential candidate for orthopedic clinical applications.

Bone cements have been used in the clinical setting to fill bone defects resulting from bone tumors. However, traditional bone cements do not have the function to kill tumor cells. This study develops a new type of tricalcium silicate (CS) based functional bone cement with excellent photothermal performance for the minimally invasive therapy of bone defects as well as bone tumors. Graphene oxide (GO) was introduced into the CS cement by co-precipitation of CS particles with GO nanosheets to form a CS/GO composite material based on charge interactions between the CS and GO. The incorporation of GO enhanced the self-setting properties of CS and endowed the cement with excellent photothermal performance with the irradiation of near-infrared light. Besides this, the temperature of the composite cement could be regulated by adjusting the laser power and the GO content, where the rising temperature significantly inhibited the growth of subcutaneous tumor tissue in vivo. In addition, the hydration process and development of the early compressive strength of the composite cement could be modulated based on its photothermal performance. Moreover, the CS/GO composite cement retained the bioactivity of CS to promote cell proliferation and the alkaline phosphate activity of MC3T3-E1. Therefore, the CS/GO composite cement holds great promise as a new type of functional bone cement with photothermal performance for bone tumor therapy and bone defect repair.

Elimination of residual osteosarcoma cells and repair of bone defects remain major challenges for osteosarcoma in clinic. To address this problem, it is required that multifunctional therapeutic platform possess high tumor-killing efficiency and simultaneous bone regeneration capabilities. In this work, an intelligent therapeutic platform was developed to achieve highly-efficient tumor therapy and simultaneous significantly improved bone defect repairing ability, which was realized by

BACKGROUND: Given their highly adjustable and predictable properties, three-dimensional(3D) printed geometrically ordered porous biomaterials offer unique opportunities as orthopedic implants. The performance of such biomaterials is, however, as much a result of the surface properties of the struts as it is of the 3D porous structure. In our previous study, we have investigated the in vitro performances of selective laser melted (SLM) Ti-6Al-4V scaffolds which are surface modified by the bioactive glass (BG) and mesoporous bioactive glass (MBG), respectively. The results demonstrated that such modification enhanced the attachment, proliferation, and differentiation of human bone marrow stromal cells (hBMSC). Here, we take the next step by assessing the therapeutic potential of 3D printed Ti-6Al-4V scaffolds with BG and MBG surface modifications for bone regeneration in a rabbit bone defect model. METHODS: 3D printed Ti-6Al-4V scaffolds with BG and MBG surface modifications were implanted into the femoral condyle of the rabbits, the Ti-6Al-4V scaffolds without surface modification were used as the control. At week 3, 6, and 9 after the implantation, micro-computed tomography (micro-CT) imaging, fluorescence double-labeling to determine the mineral apposition rate (MAR), and histological analysis of non-decalcified sections were performed. RESULTS: We found significantly higher volumes of regenerated bone, significantly higher values of the relevant bone morphometric parameters, clear signs of bone matrix apposition and maturation, and the evidence of progressed angiogenesis and blood vessel formation in the groups where the bioactive glass was added as a coating, particularly the MGB group. CONCLUSIONS: The MBG coating resulted in enhanced osteoconduction and vascularization in bone defect healing, which was attributed to the release of silicon and calcium ions and the presence of a nano-mesoporous structure on the surface of the MBG specimens.

Pure iron (Fe) has been investigated as a cardiovascular stent in recent years for its biodegradation property and blood compatibility. It also has great potential for bone healing, especially for load-bearing areas based on its inherent mechanical property which is high enough for bone regeneration. However, the conventional manufacturing methods restrict its application as bone scaffold for uncontrollable architecture and stiffness. Also, the cytotoxicity makes it impossible for in vitro culture as bone tissue engineering scaffold. To solve these deficiencies, in the present study, we applied 3D printing technique with a modified coating strategy together to precisely control the macropore structure and surface nanostructure of final scaffolds. Our results showed that the compressive mechanical properties of the 3D printed Fe scaffolds were in the natural bone range and the hydroxyapatite (HA) coating was highly bonded to the substrate, significantly improved the viability and alkaline phosphatase (ALP) activity and osteogenic differentiation of the rabbit bone marrow mesenchymal stem cells (rBMSCs) on the scaffold. This study indicates that the 3D printed Fe scaffolds with controllable nanostructured HA coating may be a promising candidate for bone tissue engineering applications.

Quick and effective sterilization of drug-resistant bacteria inevitably became an ever-growing global challenge. In this study, a multifunctional composite (PDA/Cu-CS) hydrogel mainly composed of polydopamine (PDA) and copper-doped calcium silicate ceramic (Cu-CS) was prepared. It was confirmed that PDA/copper (PDA/Cu) complexing in the composite hydrogel played a key role in enhancing the photothermal performance and antibacterial activity. Through a unique "hot ions effect", created by the heating of Cu ions through the photothermal effect of the composite hydrogel, the hydrogel showed high-efficiency, quick, and long-term inhibition of methicillin-resistant Staphylococcus aureus and Escherichia coli. In addition, the hydrogel possessed remarkable bioactivity to stimulate angiogenesis. The in vivo results confirmed that the "hot ions effect" of the composite hydrogel removed existing infection in the wound area efficiently and significantly promoted angiogenesis and collagen deposition during infectious skin wound healing. Our results suggested that the design of multifunctional hydrogels with "hot ions effect" may be an effective therapeutic approach for the treatment of infectious wounds.

Bioceramics play an important role in bone regeneration. However, it is challenging to design bioceramic scaffolds with suitable ionic components and beneficial osteo/angio-stimulation ability for enhanced bone regeneration. In this study, we successfully synthesized a pure-phase Sr

Calcium sulfate or plaster of Paris (POP) is considered as a bone cement with a fast degradation rate, which frequently makes it resorb before the bone defect area is completely filled by new bone. The incorporation of tricalcium silicate (C3S) into POP cement has been proven as a feasible approach to reduce the in vitro degradation rate and improve the in vitro bioactivity of the material. However, the in vivo performance of the POP/C3S composite cement is still unclear. Therefore, the aim of the present study is to assess the biodegradability and osteogenesis of POP/C3S composite cement in comparison with those of POP bone cement. To carry out the in vivo evaluation, POP and POP/C3S cements were implanted into a femoral condyle defect model in rabbits (5 mm diameter × 10 mm length) for 4, 8, and 12 weeks duration. The area of the remaining cement and new bone regeneration in bone defect were investigated and quantitatively measured using radiography, micro-computed tomography, and histological staining. For both cements, no sign of inflammation was observed. POP cement was completely degraded at the 8th week of post-implantation. By contrast, only approximately 50% by volume of POP/C3S composite cement degraded at the 12th week, which allowed a long-term framework for new bone formation. The osteogenic ability of POP/C3S composite cement was significantly superior to that of POP as indicated by the higher mineralization rate and maturity of the newly formed bone around the composite cement. In summary, our findings demonstrated that the in vivo degradation behaviors and osteogenic ability of POP cement could be improved by incorporating C3S in vivo, suggesting that POP/C3S composite cement has potential as a biodegradable cement for bone repair.

Background The object of the present study is to evaluate the feasibility of a silicate-based wound dressing (DermFactor ® ) in treating the wound of the patients after anorectal surgery. Materials and Methods The present study included 328 patients who received anal surgery during the period from March 2013 to June 2015. The patients were randomized to 2 groups. The patients (n = 162) in the control group received conventional dressing therapy, while those in the observation group (n = 166) were treated with the combination of conventional dressing therapy and the use of a silicate-based wound dressing (DermFactor ® ). The wound healing outcomes of the two groups were observed and compared with each other by statistical analysis. Results The average healing cycles in the observation group were 19.04 days for combined hemorrhoid patients, 23.72 days for anal fistula patients and 21.14 days for anal fissure patients, respectively, which were shorter than those in the control group (23.25 days for mixed hemorrhoid patients, 27.76 days for anal fistula patients and 24.32 days for fissure in ano patients, respectively). In addition, the observation group presented a significantly higher effective rate (80.4%) than the control group (70.4%). Conclusion Our data demonstrated that the wound after anorectal surgery could be more effectively treated by using silicate-containing DermFactor ® .

The challenges in bone tumor therapy are how to repair the large bone defects induced by surgery and kill all possible residual tumor cells. Compared to cancellous bone defect regeneration, cortical bone defect regeneration has a higher demand for bone substitute materials. To the best of our knowledge, there are currently few bifunctional biomaterials with an ultra-high strength for both tumor therapy and cortical bone regeneration. Here, we designed Fe-CaSiO3 composite scaffolds (30CS) via 3D printing technique. First, the 30CS composite scaffolds possessed a high compressive strength that provided sufficient mechanical support in bone cortical defects; second, synergistic photothermal and ROS therapies achieved an enhanced tumor therapeutic effect in vitro and in vivo. Finally, the presence of CaSiO3 in the composite scaffolds improved the degradation performance, stimulated the proliferation and differentiation of rBMSCs, and further promoted bone formation in vivo. Such 30CS scaffolds with a high compressive strength can function as versatile and efficient biomaterials for the future regeneration of cortical bone defects and the treatment of bone cancer. A method for three-dimensional printing of replacement bone that allows destruction of cancerous cells has been developed by scientists in China. Sometimes the only clinical approach to bone cancer is surgery that removes the affected tissue and replaces it with an artificial substitute. In the case of cortical bone, the dense tissue on a bone’s surface, the engineered biomaterial needs to be of very high strength. Chengtie Wu from the Shanghai Institute of Ceramics, CAS and colleagues demonstrated an iron-calcium silicate composite scaffold that is simple to produce and has the strength necessary to support the human body. The team used composite scaffold because it can be heated by near infrared light to kill residual cancer cells, a technique known as photothermal therapy. Adding iron increased the strength of the scaffold. Fe-CaSiO3 composite scaffolds (30CS) were designed via 3D printing technique. Firstly, 30CS scaffolds possessed high compressive strength to provide sufficient mechanical support in bone cortical defects; Secondly, a synergistic therapy of photothermal and ROS achieved enhanced tumor therapeutic effect in vitro and in vivo; Thirdly, the presence of CaSiO3 in the composite scaffolds enforced the degradation performance and stimulated proliferation and differentiation of rBMSCs and further promoted bone forming in vivo. Such 30CS scaffolds with high compressive strength can function as versatile and efficient biomaterials for the future regeneration of cortical bone defects and therapy of bone cancer.

The effects of titanium dioxide nanotubes (TNs) on bone repair through affecting the behaviors of mesenchymal stem cells and endothelial cells have been extensively investigated. However, their effects on cell-cell interactions have rarely been reported. Herein, the structural effects (especially the nanotube diameter) of TNs on the cellular behaviors and cell-cell interaction of human bone marrow stromal cells (HBMSCs) and human umbilical vein endothelial cells (HUVECs) were investigated. Results demonstrated that, as compared to pure Ti foil, the TNs substrates could significantly improve cell proliferation of HBMSCs and HUVECs. In addition, co-cultured HBMSCs and HUVECs showed better adhesion and spreading than mono-cultured cells when they were cultured on the same substrates. Further investigation on co-cultures suggested that the structural cues of TNs could effectively enhance the cell-cell interactions of co-cultured HBMSCs-HVUECs by stimulating cell-cell communications through cell junctions and paracrine effects, which subsequently upregulated the expression of typical osteogenic differentiation genes and vascularization genes and accelerated the vascularization of co-cultured HUVECs and osteogenic differentiation of co-cultured HBMSCs. Besides, TNs with diameter of 100 nm showed preferable stimulatory effects on cell proliferation and differentiation than TNs with diameter of 30 nm. Taken together, structural cues of TNs can significantly affect cell-cell interactions and it can be anticipated that vascularized bone tissues can be constructed by regulating the cell-cell interactions of osteogenic cells and endothelial cells with optimized TNs structural cues, which could eventually result in the enhancement of bone healing in vivo.

Quick and effective elimination of drug-resistant bacteria and simultaneous repairing the infectious tissue remain challenging in clinics. In this study, multifunctional glycol chitosan and polydopamine coated copper-doped mesoporous silica (MCS@PDA@GCS) nanoparticles with near-infrared (NIR) photothermal conversion ability and bacteria-targeting property are prepared. When infection occurred, the environment becomes acidic, and MCS@PDA@GCS nanoparticles with pH-sensitive could be accumulated on the surface of the bacteria. The NIR light-induced heating and Cu ions released from MCS@PDA@GCS nanoparticles created a distinct “hot ions effect”, showing high-efficiency, quick and long-term inhibition of bacteria (methicillin-resistant Staphylococcus aureus (MRSA) and Escherichia coli (E. coli)) as well as biofilm. In addition, the MCS@PDA@GCS nanoparticles with “mild hot ions effect” could induce macrophages polarization into a pro-inflammatory M1 phenotype, resulting in the clearance of infection through the immune-antibacterial effect. Moreover, the “mild hot ions effect” endows MCS@PDA@GCS nanoparticles with remarkable bioactivity, which stimulates the migration and angiogenesis of endothelial cells. The in vivo results confirmed that MCS@PDA@GCS nanoparticles with laser irradiation could efficiently remove bacteria and significantly promote wounds closure, epithelization and angiogenesis during infectious wound healing process.

The scar formation and hair follicle regeneration are closely related in the healing process of skin burn wounds. Excessive pathological fibroblasts at the scar site severely hinders the migration of hair follicle stem cells to the damaged site. Therefore, it is of great clinical significance to develop wound dressings to inhibit scar formation and promote hair follicle regeneration. In this study, inspired by the bioactivity of SiO32−, Fe3+ and Cur, we designed a new type of nano composites, Cur-Fe-mesoporous silica nanoparticles (Cur-Fe-SiO2, MFSC). On the one hand, Fe3+ doping reduced the stability of mesoporous silica, so that it can effectively release biologically active SiO32− and Fe3+. On the other hand, Fe3+ ions released on the surface of the mesoporous silica pores chelated with the Cur in the solution and resulted in significantly improved loading of Cur and the chelates showed higher biological activity as compared to Cur or Fe alone. The released bioactive components such as SiO32−, Fe3+ and Fe-Cur chelates showed synergistic activity in both inhibiting scar hyperplasia and promoting hair follicle regeneration. Our results suggest that the synergistic effects between ions and flavonoids can be used to increase the bioactivity of biomaterials, and design of nano composites with bioactive ions and flavonoids might be an effective approach to prepare materials for tissue regeneration.

The clinical use of cements in root canal treatment needs the dentist to mix the powders and liquid phase thoroughly. The operation not only increases the surgery time but also compromises the performance of cement in case of inhomogeneous or insufficient mixing. To overcome those drawbacks, a premixed tricalcium silicate cement (C3S) was prepared by mixing tricalcium silicate/calcium chloride (C3S/CaCl2) composites with polyethylene glycol (PEG). It was found that the setting time could be modulated by changing the content of CaCl2 in the solid phase and the liquid to solid ratio (L/P). In addition, the premixed pastes retained the bioactivity of C3S, such as the ability to induce apatite formation in simulated oral fluid and to promote the proliferation and the alkaline phosphate (ALP) activity of human dental pulp stem cells (hDPSCs). Meanwhile, the injected pastes showed good antibacterial ability against Staphylococcus aureus. It is thus expected that the premixed C3S/CaCl2 pastes hold great promise as a new type of materials for dental application.

Silicate materials have shown excellent bioactivity to enhance bone regeneration by releasing bioactive ions to stimulate osteogenesis and angiogenesis. However, one of the remaining challenges is how to control the ion release from biomaterials in order to elucidate the relationship between the ion concentration and bioactivity. In this study, we report, for the first time, the synthesis of Ca-Sr-Si biomaterials by containerless processing (CP) technique and sol-gel (SG) method, and a systematic study on ion release behaviors of the materials. The phase and chemical compositions of the materials and the dissolution condition on ion release behaviors of the biomaterials were investigated. The results showed that CP was an effective method to prepare Ca-Sr-Si glass materials. The heat treatment promoted the phase transition of the glasses, and the ion release behaviors of the biomaterials can be tailored by controlling the chemical composition, phase composition, pH value and preparation methods.

Silicate bioactive materials have been widely studied for bone regeneration because of their eminent physicochemical properties and outstanding osteogenic bioactivity, and different methods have been developed to prepare porous silicate bioactive ceramics scaffolds for bone-tissue engineering applications. Among all of these methods, the 3D-printing technique is obviously the most efficient way to control the porous structure. However, 3D-printed bioceramic porous scaffolds need high-temperature sintering, which will cause volume shrinkage and reduce the controllability of the pore structure accuracy. Unlike silicate bioceramic, bioactive silicate cements such as tricalcium silicate (Ca3SiO5 and C3S) can be self-set in water to obtain high mechanical strength under mild conditions. Another advantage of using C3S to prepare 3D scaffolds is the possibility of simultaneous drug loading. Herein, we, for the first time, demonstrated successful preparation of uniform 3D-printed C3S bone cement scaffolds with co...

Previous studies have shown that tricalcium silicate bone cements possess good bioactivity and appropriate degradation rate. However, they also showed some weaknesses such as poor washout resistance, formability and injectability, which have seriously hindered their clinical applications. The purpose of this study was to develop a new type of bone cements-tricalcium silicate/sodium alginate (C3 S/SA) composites by utilizing the interaction of Ca ions with SA molecules, in which an interpenetrating double-network of calcium hydrate silicate (CSH) and alginate hydrogel was formed to enhance the washout resistance, formability, injectability and compressive strength of C3 S. The results confirmed that the washout resistance, formability and injectability of C3 S could indeed be greatly enhanced by the introduction of SA. In addition, the compressive strength of the C3 S/SA composite cement with an optimum composition could reach 54 MPa, which was significantly higher than that of C3 S (i.e., 35.3 MPa). Moreover, the C3 S/SA composite cements retained the bioactivity of C3 S, such as the activity to induce apatite formation in simulated body fluid and to promote cell proliferation. All these results indicate that the C3 S/SA composite cements hold great promise as a new type of bone repair materials for further in vitro and in vivo studies. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 237-244, 2018.

After surgical resection for a bone tumor, the uncleared bone tumor cells can multiply and cause recurrence of the bone tumor. It is worthwhile to design a scaffold that kills the remaining bone tumor cells and repairs bone defects that were given rise to by surgical resection. Additionally, it is extremely important to consider the function of angiogenesis in the process of bone regeneration because the newly formed blood vessels can offer the nutrients for bone regeneration. In this work, a novel metal-organic framework Cu-TCPP nanosheets interface-structured β-tricalcium phosphate (TCP) (Cu-TCPP-TCP) scaffold was successfully prepared through integrating a 3D-printing technique with an in-situ growth method in a solvothermal system. Owing to the excellent photothermal effect of Cu-TCPP nanosheets, Cu-TCPP-TCP scaffolds that were illuminated by near-infrared (NIR) light demonstrated photothermal performance, which was well regulated through varying the contents of Cu-TCPP nanosheets, and the ambient humidity and power density of NIR light. When cultured with osteosarcoma cells, Cu-TCPP-TCP scaffolds killed a significant quantity of osteosarcoma cells through released heat energy after exposure to NIR light with power density 1.0 W cm-2 and duration 10 min. Similarly, Cu-TCPP-TCP scaffolds ablated subcutaneous bone tumor tissues on the backs of naked mice and suppressed their growth because of the heat energy transformed from NIR light. I n-vitro studies found that Cu-TCPP-TCP scaffolds ably supported the attachments of both human bone marrow stromal cells (HBMSCs) and human umbilical vein endothelial cells (HUVECs), and significantly stimulated expressions of osteogenesis differentiation-related genes in HBMSCs and angiogenesis differentiation-related genes in HUVECs. After implanting Cu-TCPP-TCP scaffolds into the bone defects of rabbits, they effectively promoted bone regeneration. Thus, the integration of the bone-forming bioactivity of TCP scaffolds with the photothermal properties of Cu-TCPP nanosheets and angiogenesis activity of Cu ions makes Cu-TCPP-TCP scaffolds multifunctional, representing a new horizon to develop biomaterials for simultaneously curing bone tumors and repairing bone defects.

The effects of titanium dioxide nanotubes (TNs) on bone repair through affecting the behaviors of mesenchymal stem cells and endothelial cells have been extensively investigated. However, their effects on cell-cell interactions have rarely been reported. Herein, the structural effects (especially the nanotube diameter) of TNs on the cellular behaviors and cell-cell interaction of human bone marrow stromal cells (HBMSCs) and human umbilical vein endothelial cells (HUVECs) were investigated. Results demonstrated that, as compared to pure Ti foil, the TNs substrates could significantly improve cell proliferation of HBMSCs and HUVECs. In addition, co-cultured HBMSCs and HUVECs showed better adhesion and spreading than mono-cultured cells when they were cultured on the same substrates. Further investigation on co-cultures suggested that the structural cues of TNs could effectively enhance the cell-cell interactions of co-cultured HBMSCs-HVUECs by stimulating cell-cell communications through cell junctions and paracrine effects, which subsequently upregulated the expression of typical osteogenic differentiation genes and vascularization genes and accelerated the vascularization of co-cultured HUVECs and osteogenic differentiation of co-cultured HBMSCs. Besides, TNs with diameter of 100 nm showed preferable stimulatory effects on cell proliferation and differentiation than TNs with diameter of 30 nm. Taken together, structural cues of TNs can significantly affect cell-cell interactions and it can be anticipated that vascularized bone tissues can be constructed by regulating the cell-cell interactions of osteogenic cells and endothelial cells with optimized TNs structural cues, which could eventually result in the enhancement of bone healing

Incorporating Sr element in biomaterials for bone implants is an effective way to improve their biological performance, as Sr element has been proved to enhance bone regeneration and depress bone resorption activity. In the present study, we developed a Sr-incorporated dicalcium silicate (C2S) bone cement as a potential candidate for bioactive self-setting bone cement in orthopaedics and stomatology. The Sr-C2S powders containing 0.3&ndash, 6.8% Sr in molar ratio were prepared by means of chemical co-precipitation, and the results of XRD analysis indicated the incorporation of Sr element into the lattice of C2S. Sr-C2S bone cements, as prepared by mixing the powders with water, have a final setting time of 570 to 594 min, and compressive strength higher than that of C2S bone cement within certain incorporation range. The Sr-C2S bone cements possessed good in vitro bioactivity by inducing apatite formation in simulated body fluid (SBF) within 7 days. Moreover, the proliferation activity of human bone marrow mesenchymal stem cells (hBMSCs) with Sr-C2S bone cements was significantly higher than that with C2S bone cement, and the alkaline phosphatase (ALP) activity of hBMSCs was also enhanced with addition of Sr element in Sr-C2S groups. The Sr-C2S might therefore be a bioactive self-setting material with enhanced biological performance and holds the prospect for application in the bone regeneration area.

Due to the complexity of the skin tissue structure, the regeneration of the entire skin, including skin appendages such as hair follicles, is a big challenge. In addition, skin trauma is often accompanied by bacterial infections that delay the wound healing. Therefore, developing wound dressings, which promote hair follicle regeneration and inhibit bacterial infection in the wound healing process, is of great clinical significance. In this study, Zn doped hollow mesoporous silica nanospheres (HMZS) were synthesized by a sol-gel method and a novel wound healing dressing was prepared by incorporation of drug ciprofloxacin hydrochloride (CiH)-loaded Zn containing mesoporous silica nanospheres (CiH-HMZS) into polycaprolactone (PCL) electrospun fibers. The CiH-HMZS/P nano-composite electrospun fibers exhibit the ability to promote angiogenesis and skin regeneration by releasing Si ions, and the activity to enhance hair follicle regeneration and inhibit bacterial growth by releasing zinc ions and achieve the synergistic antibacterial effect with both Zn ions and CiH in low concentrations. Thus, the CiH-HMZS/P nano-composite membrane is a promising multi-functional wound healing material for inhibiting bacterial growth in infected wounds and enhancing skin wound healing including hair follicle regeneration.

After online publication of this article, the authors noticed an error of Fig. 3h in Fig. 3. The correct Fig. 3 of this article should have read as below.

Implant-related infections (IRIs) and implant osseointegration disorders are the most common and catastrophic complications after total joint arthroplasty (TJA). Macrophages play a vital role in the development of these complications. Herein, tailored to the immunological characteristics of IRIs and implant osseointegration disorders, we proposed a sequential immunomodulatory strategy to cope with the complications, using Cu-Zn bi-layer nanofibrous membranes synthesized via a facile electrospinning process and a hot-pressed method. It was found that Cu-Zn bi-layer nanofibrous membranes exhibited a desirable controlled release of Cu2+ and Zn2+, and could sequentially regulate macrophage phenotype shift from M1 to M2 through alternately activating the MAPK and mTOR signaling pathways. Moreover, the dual-temporal bidirectional immunomodulatory effect endowed the Cu-Zn bi-layer nanofibrous membranes excellent anti-infection and osteogenic abilities in vitro and in vivo. To our knowledge, this is the first dual-temporal bidirectional immunomodulatory biomaterial specifically designed for the immune requirements of IRIs and implant osseointegration disorders. This is a meaningful attempt, which may pave a new way for exploring novel immunomodulatory biomaterials to solve the clinical challenges.

Background Given their highly adjustable and predictable properties, three-dimensional(3D) printed geometrically ordered porous biomaterials offer unique opportunities as orthopedic implants. The performance of such biomaterials is, however, as much a result of the surface properties of the struts as it is of the 3D porous structure. In our previous study, we have investigated the in vitro performances of selective laser melted (SLM) Ti-6Al-4V scaffolds which are surface modified by the bioactive glass (BG) and mesoporous bioactive glass (MBG), respectively. The results demonstrated that such modification enhanced the attachment, proliferation, and differentiation of human bone marrow stromal cells (hBMSC). Here, we take the next step by assessing the therapeutic potential of 3D printed Ti-6Al-4V scaffolds with BG and MBG surface modifications for bone regeneration in a rabbit bone defect model. Methods 3D printed Ti-6Al-4V scaffolds with BG and MBG surface modifications were implanted into the femoral condyle of the rabbits, the Ti-6Al-4V scaffolds without surface modification were used as the control. At week 3, 6, and 9 after the implantation, micro-computed tomography (micro-CT) imaging, fluorescence double-labeling to determine the mineral apposition rate (MAR), and histological analysis of non-decalcified sections were performed. Results We found significantly higher volumes of regenerated bone, significantly higher values of the relevant bone morphometric parameters, clear signs of bone matrix apposition and maturation, and the evidence of progressed angiogenesis and blood vessel formation in the groups where the bioactive glass was added as a coating, particularly the MGB group. Conclusions The MBG coating resulted in enhanced osteoconduction and vascularization in bone defect healing, which was attributed to the release of silicon and calcium ions and the presence of a nano-mesoporous structure on the surface of the MBG specimens.

Biodegradable metal matrix composites (MMCs) with pure magnesium as the matrix and bioceramic calcium silicate (CS) as the reinforcement phase were fabricated by means of spark plasma sintering (SPS). The microstructure, mechanical properties and degradation behavior of the composites as well as the cellular responses to these composites were investigated. The formation of CS networks in the Mg matrix was observed when the CS content reached 20%. Among the composites with CS weight percentages ranging from 10% to 40%, the composite containing 20% CS possessed the highest structural compactness and compressive strength. Immersion tests in simulated body fluid (SBF) revealed that the Mg–20% CS composite exhibited a substantially enhanced corrosion resistance as compared with pure Mg, which was attributed to the formation of a hydroxyapatite (HA) layer on the surface as a result of the presence of the CS networks throughout the Mg matrix. In addition, ionic products from the interaction between the Mg–20% CS composite and SBF brought about a significant stimulatory effect on the alkaline phosphate (ALP) expression of MC3T3-E1 osteoblast cells. Our results indicate that CS is an effective reinforcement phase to improve both the corrosion resistance and bioactivity of Mg and the Mg–CS composites developed in this research are able to overcome the inherent drawbacks of magnesium as a biodegradable implant material.

Bioceramics play an important role in bone regeneration. However, it is challenging to design bioceramic scaffolds with suitable ionic components and beneficial osteo/angio-stimulation ability for enhanced bone regeneration. In this study, we successfully synthesized a pure-phase Sr5(PO4)2SiO4 (SPS) bioactive ceramic through a solid-state reaction method and further prepared highly uniform SPS bioceramic scaffolds with controlled macropore sizes and mechanical strength by a 3D-plotting technique, and the biological responses of rabbit bone marrow stromal cells (rBMSCs) and human umbilical vein endothelial cells (HUVECs) after culturing with different concentrations of SPS extracts and porous scaffolds were systematically studied. The results showed that the ionic products from SPS bioceramics significantly stimulated the proliferation, alkaline phosphate (ALP) activity and osteogenesis-related gene expression (Runx2, ALP, OCN, OPN) of rBMSCs as well as the proliferation and angiogenesis-related gene expression (VEGF, KDR, eNOS, HIF 1α) of HUVECs. 3D-plotted SPS scaffolds could effectively support the attachment and proliferation of both rBMSCs and HUVECs, and the proliferation rates of the two kinds of cells in SPS scaffolds were distinctively higher than those in β-tricalcium phosphate (β-TCP) scaffolds prepared by the same method. In addition, the compressive strength of SPS scaffolds could be well controlled in the range 8–30 MPa when their pore size varied from 100 to 300 μm, which was significantly higher than those of β-TCP scaffolds with similar pore sizes (∼1.5 times). Our results demonstrated that 3D-plotted SPS bioceramic scaffolds with such a specific ionic combination and high mechanical strength as well as good degradability possessed the ability to stimulate both osteogenic and angiogenic differentiation of tissue cells, indicating that they might be promising biomaterials for bone tissue engineering.