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The 3D printing technology with unique strategies for accurate fabrication of biomaterials in regenerative medicine has been widely applied in bone regeneration. However, the traditional 3D printing scaffolds are only stacked by solid struts without any hollow channel structures, which limits the new bone tissue formation. In this study, a special 3D scaffold with hollow channels and a micro-nano surface was prepared by a modified 3D printing strategy combined with the hydrothermal treatment approach. By regulating the reaction solution of hydrothermal treatment, the micro-nano structures formed on the surface of scaffolds can be successfully controlled. Moreover, the scaffolds have the ability to facilitate the attachment and proliferation of BMSCs after culturing for 1, 3, and 7 days in vitro. Interestingly, the in vivo results demonstrated that the hollow channels and the micro-nano surface present synergistic effects on bone regeneration. They both boost the new bone formation in femur defects in rabbits for 12 weeks after operation. The study demonstrates a 3D scaffold with special surface microstructures and hollow struts that can overcome the shortages of most traditional scaffolds and meanwhile improve the bioactivity of biomaterials for bone tissue engineering.

Articular cartilage lesions occur frequently but unfortunately the damaged cartilage has a very limited intrinsic repair capacity. Since the cartilage damage can cause sterile inflammation, the effects of inflammation on cartilage repair should be well understood for precise treatment. Our previous study showed that bioceramics play an important role in cartilage regeneration. However, it is unclear how the immune microenvironment induced by bioactive ceramics influences cartilage regeneration. In this study, we applied the model bioactive ceramic lithium calcium silicate (Li2Ca4Si4O13, LCS) to prepare scaffolds and explore whether LCS scaffolds could promote cartilage maturation by regulating macrophage polarization. It was found that LCS induced the shifting of macrophages to anti-inflammatory M2 phenotype by downregulating the expressions of inflammatory genes TNFα, IL-6 and IL-1β and promoting the expression of IL-10 genes. The conditioned medium from LCS-treated macrophages promoted the proliferation, migration and maturation of chondrocytes. In a chondrocyte and macrophage co-culture system, LCS scaffolds induced chondrocyte maturation. These results demonstrated that LCS significantly promoted chondrocyte maturation by immunomodulating the M2 macrophage polarization. Hence, LCS scaffolds have great potential in cartilage repair, indicating that bioceramics may be used in cartilage regeneration due to their immunomodulatory effects on macrophages.

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.

Various therapeutic techniques have been studied for treating cancer precisely and effectively, such as targeted drug delivery, phototherapy, tumor-specific catalytic therapy, and synergistic therapy, which, however, evoke numerous challenges due to the inherent limitations of these therapeutic modalities and intricate biological circumstances as well. With the remarkable advances of nanotechnology, nanoplatform-based cascade engineering, as an efficient and booming strategy, has been tactfully introduced to optimize these cancer therapies. Based on the designed nanoplatforms, pre-supposed cascade processes could be triggered under specific conditions to generate/deliver more therapeutic species or produce stronger tumoricidal effects inside tumors, aiming to achieve cancer therapy with increased anti-tumor efficacy and diminished side effects. In this review, the recent advances in nanoplatform-based cascade engineering for cancer therapy are summarized and discussed, with an emphasis on the design of smart nanoplatforms with unique structures, compositions and properties, and the implementation of specific cascade processes by means of endogenous tumor microenvironment (TME) resources and/or exogenous energy inputs. This fascinating strategy presents unprecedented potential in the enhancement of cancer therapies, and offers better controllability, specificity and effectiveness of therapeutic functions compared to the corresponding single components/functions. In the end, challenges and prospects of such a burgeoning strategy in the field of cancer therapy will be discussed, hopefully to facilitate its further development to meet the personalized treatment demands.

For the research of biomaterials in bone tissue engineering, it is still a challenge to fabricate bioceramics that overcome brittleness while maintaining the great biological performance. Here, inspired by the toughness of natural materials with hierarchical laminated structure, we presented a directional assembly-sintering approach to fabricate laminated MXene/calcium silicate-based (L-M/CS) bioceramics. Benefiting from the orderly laminated structure, the L-M/CS bioceramics exhibited significantly enhanced toughness (2.23 MPa·m1/2) and high flexural strength (145 MPa), which were close to the mechanical properties of cortical bone. Furthermore, the L-M/CS bioceramics possessed more suitable degradability than traditional CaSiO3 bioceramics due to the newly formed CaTiSiO5 after sintering. Moreover, the L-M/CS bioceramics showed good biocompatibility and could stimulate the expression of osteogenesis-related genes. The mechanism of promoting osteogenic differentiation had been shown to be related to the Wnt signaling pathway. This work not only fabricated calcium silicate-based bioceramics with excellent mechanical and biological properties for bone tissue engineering but also provided a strategy for the combination of bionics and bioceramics.

Developing multifunctional wound dressing with desired mechanical strength is of great significance for the treatment of different types of skin wounds. Inspired by the close relationship between strength and hierarchical structure of nacre, hierarchical and porous graphene oxide-chitosan-calcium silicate (GO-CTS-CS) film biomaterials are fabricated by a combination of vacuum filtration-assisted assembly and freeze-drying methods. The bioinspired hierarchical materials emulate an orderly porous lamellar micron-scale structure and the "brick-and-mortar"-layered nanostructure. The hierarchical microstructure endows the GO-CTS-CS biomaterials with good tensile strength, compatible breathability, and water absorption. Furthermore, the hierarchical GO-CTS-CS biomaterials exhibit ideal photothermal performance, leading to significant photothermal antibacterial and antitumor efficacy. Further, the hierarchical GO-CTS-CS biomaterials show stimulatory effect on in vivo chronic wound healing. Therefore, such a high performance and multifunctional biomaterial is believed to offer a promising alternative to traditional wound dressing in future. STATEMENT OF SIGNIFICANCE: Although it is an effective strategy to prepare high-performance materials by mimicking the hierarchical microstructure of nacre, the preparation of nacre-inspired materials in tissue engineering fields still needs to be investigated. In this work, we prepared a nacre-inspired multifunctional graphene oxide-chitosan-calcium silicate (GO-CTS-CS) biomaterial with a hierarchical microstructure. The hierarchical microstructure endows the biomaterials with desired properties of strength, breathability, and water absorption. Further, the hierarchical GO-CTS-CS biomaterial showed good photothermal antibacterial/antitumor and wound healing effects. This work may provide an approach to combine the preparation of multifunctional biomaterials with bioinspired engineering by constructing a hierarchical microstructure, indicating that the assembling hierarchical microstructure in biomaterials is of great importance for tissue engineering and regenerative medicine.

The treatment of severe burn injuries is a crucial challenge in skin tissue engineering. Severe burns are always accompanied with large-area neurovascular networks damage, leading to the lack of excitation functions and difficulty in self-healing. Therefore, it is of great importance to develop biomaterials which can not only promote wound healing but also simultaneously reconstruct cutaneous neurovascular networks. In this study, Zn

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.

Osteoarthritis (OA) is a degenerative disease that involves excess reactive oxygen species (ROS) and osteochondral defects. Although multiple approaches have been developed for osteochondral regeneration, how to balance the biochemical and physical microenvironment in OA remains a big challenge. In this study, a bioceramic scaffold by 3D printed akermanite (AKT) integrated with hair-derived antioxidative nanoparticles (HNPs)/microparticles (HMPs) for ROS scavenging and osteochondral regeneration has been developed. The prepared bioscaffold with multi-mimetic enzyme effects, which can scavenge a broad spectrum of free radicals in OA, can protect chondrocytes under the ROS microenvironment. Importantly, the bioscaffold can distinctly stimulate the proliferation and maturation of chondrocytes due to the stimulation of the glucose transporter pathway (GLUT) via HNPs/HMPs. Furthermore, it significantly accelerated osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). In vivo results showed that the bioscaffold can effectively enhance the osteochondral regeneration compared to the unmodified scaffold. The work shows that integration of antioxidant and mechanical properties via the bioscaffold is a promising strategy for osteochondral regeneration in OA treatment.

Exosomes have attracted increasing attention in tissue regeneration and repair due to their roles in intercellular communication. Developing a customized delivery system is key to exosome-based regenerative therapeutics. Bioceramics play an important role in the immunomodulation of macrophages. Here, three-dimensional (3D) printing was applied to construct porous scaffolds with β-tricalcium phosphate (β-TCP) bioceramic-induced macrophage exosomes (BC-Exos). The three-dimensional-printed BC-Exo scaffolds, exhibiting a predefined structure and persistent release of exosomes, displayed distinct immunomodulatory effects and improved osteogenesis/angiogenesis. The BC-Exos in the printed scaffolds modulated macrophage polarization and the expression of chemokines for the recruitment of bone marrow mesenchymal stem cells (BMSCs) and endothelial cells. Scaffolds with BC-Exos from macrophages with a mixed phenotype significantly enhanced the osteogenic differentiation and immunosuppression of BMSCs and improved the angiogenic activity of human umbilical vein endothelial cells in vitro. For the potential mechanism, β-TCP bioceramics have an important effect on the immunomodulation of macrophages by regulating gene expression, increasing exosome production, and altering exosomal miRNA cargos, thereby affecting the paracrine effects of BC-Exos on immunomodulation and osteogenesis/angiogenesis. This study suggests that 3D printing of bioceramic-induced macrophage exosomes may be a useful strategy for tissue engineering and regenerative medicine. 3D printing of bioceramic-induced macrophage exosomes (BC-Exos) displayed stimulatory effects on immunomodulation, osteogenesis, and angiogenesis of macrophage (MΦs), mesenchymal stem cells (MSCs) and endothelial cells (ECs), respectively. BC-Exos enhanced the expression of chemotaxis, osteogenic and angiogenic genes by altering their miRNAs profile. 3D printing of BC-Exos offers a new cell-free strategy for tissue regeneration.

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.

Various bifunctional scaffolds have recently been developed to address the reconstruction of tumor‐initiated bone defects. Such scaffolds are usually composed of a near‐infrared (NIR) photothermal conversion agent and a conventional bone scaffold for photothermal therapy (PTT) and long‐term bone regeneration. However, the reported photothermal conversion agents are mainly restricted to the first biological window (NIR‐I) with intrinsic poor tissue penetration depth. Also, most of these agents are non‐bioactive materials, which induced potential systemic side toxicity after implantation. Herein, a NIR‐II photothermal conversion agent (Wesselsite [SrCuSi4O10] nanosheets, SC NSs) with tremendous osteogenic and angiogenic bioactivity, is rationally integrated with polycaprolactone (PCL) via 3D printing. The as‐designed 3D composite scaffolds not only trigger osteosarcoma ablation through NIR‐II light generated extensive hyperthermia, but also promote in vitro cellular proliferation and osteogenic differentiation of rat bone marrow mesenchymal stem cells (rBMSCs) and human umbilical vein endothelial cells (HUVECs), respectively, and the ultimate enhancement of vascularized bone regeneration in vivo owing to the controlled and sustained release of bioactive ions (Sr, Cu, and Si). The authors' study provides a new avenue to prepare multifunctional bone scaffolds based on therapeutic bioceramics for repairing tumor‐induced bone defects., An efficient multifunctional bone scaffold based on 3D printed SrCuSi4O10 nanosheets/polycaprolactone composite is developed as SC/PCL, which possesses excellent therapeutic effects for deep‐seated osteosarcoma due to its high photothermal‐conversion efficiency in the second biological window. Moreover, the as‐designed 3D composite scaffold could facilitate the vascularized bone regeneration via the sustained release of bioactive ions (Sr, Si, and Cu).

Recently, strategies that can target the underlying mechanisms of phenotype change to modulate the macrophage immune response from the standpoint of biological science have attracted increasing attention in the field of biomaterials. In this study, we printed a molybdenum-containing bioactive glass ceramic (Mo-BGC) scaffold as an immunomodulatory material. In a clinically relevant critical-size periodontal defect model, the defect-matched scaffold featured robust immunomodulatory activity, enabling long-term stable macrophage modulation and leading to enhanced regeneration of multiple periodontal tissues in canines. Further studies demonstrated that the regeneration-enhancing function of Mo-BGC scaffold was macrophage-dependent by using canines with host macrophage depletion. To investigate the role of Mo in material immunomodulation, in vitro investigations were performed and revealed that Mo-BGC powder extract, similar to MoO

It is common to improve the relevant performance in the field of energy storage materials or catalytic materials by regulating the number of defects. However, there are few studies on the biomaterials containing defects for tissue engineering. Herein, a new type of defect-rich scaffolds, black akermanite (B-AKT) bioceramic scaffolds with micro/nanostructure, the thickness of which is from 0.14 to 1.94 µm, is fabricated through introducing defects on the surface of bioceramic scaffolds. The B-AKT scaffolds have advantages on the degradation rate and the osteogenic capacity over the AKT (Ca2 MgSi2 O7 ) scaffolds due to the surface defects which stimulate the osteogenic differentiation of rabbit bone mesenchymal stem cells via activating bone morphogenetic protein 2 （BMP2） signaling pathway and further promote bone formation in vivo. In addition, the prepared B-AKT scaffolds, the temperature of which can be over 100 °C under the near infrared （NIR） irradiation (0.66 W cm-2 ), possess excellent performance on photothermal and antitumor effects. The work develops an introducing-defect strategy for regulating the biological performance of bioceramic scaffolds, which is expected to be applied in the next generation of bioceramic scaffolds for regenerative medicine.

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.

The clinical treatment of bone tumors usually brings about residual tumor cells and large bone defects after tumor removal surgery. To solve this problem, it is imperative to develop a novel implant with bi-functions for eliminating the residual tumor cells and repairing bone defects. In this study, hydrogenated black TiO2 (H-TiO2) coating with hierarchical micro/nano-topographies is fabricated by induction suspension plasma spraying (ISPS). The fabricated H-TiO2 coating possessed excellent and controllable photothermal effect in inhibiting the tumor growth under 808 nm NIR laser irradiation in vitro and in vivo. The hierarchical hybrid micro/nano-structured surface and Ti-OH groups improved the adhesion, proliferation, differentiation and osteogenic gene expressions of rat bone mesenchymal stem cells (rBMSCs). These results demonstrate that the H-TiO2 coating may be a promising implant material for the treatment of bone tumors and bone regeneration.

Bioceramics have been used for the replacement and repair of damaged hard tissues for about 50 years, in which the mechanical properties and biocompatibility of the materials are critical factors to be considered for their clinical applications. Recently, more and more studies have demonstrated that bioceramics with specific chemical composition and topographical structure have activity to regulate the fate of stem cells and the interaction with their microenvironment, which result in enhanced tissue regeneration including hard and soft tissues. These findings open up a new direction to explore the possibility of designing new biomaterials for tissue engineering and regenerative medicine based on the specific biological function of the chemical and topographical characteristics of the biomaterials. In this review, we focus on the roles of the chemical characteristics such as bioactive ions released from bioceramics and the structural characteristics such as micro/nano surface topography of bioceramics in regulating stem cells and their microenvironment to enhance tissue regeneration. Furthermore, considering the bioactivity of ions on soft tissue related cells, the design and potential applications of bioceramics for soft tissue regeneration are also discussed, and the future perspectives of the bioceramics research from the points of both materials engineering and biological science are proposed.

Treatment for osteochondral defects remains a great challenge. Although several clinical strategies have been developed for management of osteochondral defects, the reconstruction of both cartilage and subchondral bone has proved to be difficult due to their different physiological structures and functions. Considering the restriction of cartilage to self-healing and the different biological properties in osteochondral tissue, new therapy strategies are essential to be developed. This review will focus on the latest developments of bioactive scaffolds, which facilitate the osteogenic and chondrogenic differentiation for the regeneration of bone and cartilage. Besides, the topic will also review the basic anatomy, strategies and challenges for osteochondral reconstruction, the selection of cells, biochemical factors and bioactive materials, as well as the design and preparation of bioactive scaffolds. Specifically, we summarize the most recent developments of single-type bioactive scaffolds for simultaneously regenerating cartilage and subchondral bone. Moreover, the future outlook of bioactive scaffolds in osteochondral tissue engineering will be discussed. This review offers a comprehensive summary of the most recent trend in osteochondral defect reconstruction, paving the way for the bioactive scaffolds in clinical therapy. The translational potential of this article: This review summaries the latest developments of single-type bioactive scaffolds for regeneration of osteochondral defects. We also highlight a new possible translational direction for cartilage formation by harnessing bioactive ions and propose novel paradigms for subchondral bone regeneration in application of bioceramic scaffolds. Keywords: Bioactive scaffolds, Bioceramics, Cartilage repair, Osteochondral regeneration, Subchondral bone regeneration

Tricalcium silicate (C3S) and hydroxyapatite (HAp) composites were fabricated through the sol-gel process. The aim of this research is to improve the biocompatibility of C3S through HAp addition and study the potential of using this as coating materials. The composites (HAp/C3S) were characterised by Fourier transform infrared spectrometry, thermal gravity-differential thermal analysis and X-ray diffraction. The working and setting times of cement pastes were tested using Gillmore needle. Mechanical properties were examined by nanoindentation and material testing system. In vitro biocompatibility of the materials were studied by cell attachment and viability of L929 and MG-63 cells. HAp/C3S as a coating material on gelatin film were measured with the surface roughness and imaged by scanning electron microscope. With the addition of HAp, no undesirable free CaO was detected with the synthesis by the sol-gel preparation. The pH values of HAp added groups were between 7.54 and 8.76, which were much lower than pure C3S group (pH = 11.75). For in vitro studies, the presence of HAp could effectively enhance the cell attachment and viability of both L929 and MG-63 cells grown in the extract or directly on the composites. However, the mechanical properties of the composites were impaired as compared to pure C3S. Lastly, HAp/C3S cement could be evenly coated on gelatin film. HAp is successfully demonstrated to improve C3S biocompatibility with this new composites HAp/C3S. C-75 (75% C3S and 25% HAp), in particular, has good biocompatibility, relatively high compressive strength and can be uniformly coated onto gelatin film. Thus, C-75 is a promising material for further investigation as a coating on other biopolymers.

Surgery is a common treatment to remove the solid skin tumors. It is of great importance to eliminate the remaining tumor cells and achieve the simultaneous tissue reconstruction after surgery for improving life quality of cancer patients. Inspired by the designing strategy and fabrication method of Chinese sesame sticks, a Chinese sesame stick-like scaffold is developed by spin coating of CaCuSi4O10 nanoparticles (NPs) on the surface of electrospun fibers for tumor therapy and skin tissue reconstruction. The CaCuSi4O10 NPs can transform near-infrared light energy into heat energy, showing the photothermal conversion efficiency of 33.8%. After coating of the CaCuSi4O10 NPs on the fibers, the prepared scaffolds exhibit the Chinese sesame stick-like structure and achieve bifunction with both tumor killing and skin tissue reconstruction capacities. The CaCuSi4O10 NPs endow the scaffolds with photothermal ablation potential to rapidly kill the in vitro tumor cells. Furthermore, Chinese sesame stick-like scaffolds effectively inhibit in vivo tumor growth at the early stage and accelerate healing of cancer surgery-caused wounds at the later stage in tumor-bearing mice. Additionally, the composite scaffolds promote chronic wound healing by stimulating in vivo angiogenesis and re-epithelization, harnessing locally release of bioactive Cu2+ and SiO44- ions from the CaCuSi4O10 NPs. Therefore, the Chinese sesame stick-inspired scaffolds may lay a solid foundation for clinical treatment of cancers and cancer surgery-induced tissue damage.

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

Bioactive glasses have been used for bone regeneration applications thanks to their excellent osteoconductivity, an osteostimulatory effect, and high degradation rate, releasing biologically active ions. Besides these properties, mesoporous bioactive glasses (MBG) are specific for their highly ordered mesoporous channel structure and high specific surface area, making them suitable for drug and growth factor delivery. In the present study, calcium (Ca) (15 mol%) in MBG was partially and fully substituted with zinc (Zn), known for its osteogenic and antimicrobial properties. Different MBG were synthesized, containing 0, 5, 10, or 15 mol% of Zn. Up to 7 wt.% of Zn-containing MBG could be mixed into an alginate-methylcellulose blend (algMC) while maintaining rheological properties suitable for 3D printing of scaffolds with sufficient shape fidelity. The suitability of these composites for bioprinting applications has been demonstrated with immortalized human mesenchymal stem cells. Uptake of Ca and phosphorus (P) (phosphate) ions by composite scaffolds was observed, while the released concentration of Zn2+ corresponded to the initial amount of this ion in prepared glasses, suggesting that it can be controlled at the MBG synthesis step. The study introduces a tailorable bioprintable material system suitable for bone tissue engineering applications.

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.

Silicon (Si)-based biomaterials have been widely applied for bone regeneration. However, the underlying mechanisms remain unknown. T lymphocyte-mediated adaptive immune response plays a vital role in the process of bone regeneration. In the present study, mesoporous silica (MS) was used as a model material of Si-based biomaterials. It showed that the supernatant of CD4 + T cells pretreated with MS extract significantly promoted the vascularized bone regeneration. The potential mechanism is closely related to the fact that MS extract could reduce the expression of regulatory factor X-1 (RFX-1) in CD4 + T cells, which could lead to interleukin-17A (IL-17A) overexpression through increased histone H3 acetylation and decreased DNA methylation and H3K9 trimethylation. Importantly, the in vivo experiments further revealed that MS particles dramatically stimulated bone regeneration with improved angiogenesis in the critical-sized calvarial defect mouse model accompanied by upregulation of IL-17A in peripheral blood and the proportion of Th17 cells.

Bioceramics have been developed from bioinert to bioactive or biodegradable materials in the past few decades. However, at present, traditional bioceramics are still mainly used in bone tissue regeneration and dental restoration. In this work, a new generation of "black bioceramics," extending the applications from tissue regeneration to disease therapy, is presented. Black bioceramics, through magnesium thermal reduction of traditional white ceramics, including silicate-based (e.g., CaSiO3 , MgSiO3 ) and phosphate-based (e.g., Ca3 (PO4 )2 , Ca5 (PO4 )3 (OH)), are successfully synthesized. Due to the presence of oxygen vacancies and structural defects, the black bioceramics possess photothermal functionality while maintaining their initial high bioactivity and regenerative capacity. These black bioceramics show excellent photothermal antitumor effects for both skin and bone tumors. At the same time, they have significantly improved bioactivity for skin/bone tissue repair in vitro and in vivo. These fascinating properties award the black bioceramics with profound applications in both tumor therapy and tissue regeneration, which should greatly promote the scientific relevance and clinical application of bioceramics, representing a promising new direction of cell-instructive biomaterials.

Hydroxyapatite (HA) is the main inorganic component of human bone. Inspired by nacre and cortical bone, hydroxyapatite-based coil scaffolds were successfully prepared. The scaffolds presented "brick and mortar" multi-layered structure of nacre and multi-layered concentric circular structure of cortical bone. Because of bioactive components and hierarchical structure, the scaffolds possessed good compressive strength (≈95 MPa), flexural strength (≈161 MPa) and toughness (≈1.1 MJ/m3). In addition, they showed improved angiogenesis and osteogenesis in rat and rabbit critical sized bone defect models. By mimicking co-biological systems, this work provided a feasible strategy to optimize the properties of traditional tissue engineering biological materials for vascularized bone regeneration.

Magnesium silicate nanostructured biomaterials with good biocompatibility and high adsorption capacity for drugs and proteins are promising for applications in various biomedical fields. However, the applications of magnesium silicate nanostructured biomaterials in anticancer drug delivery and protein adsorption have rarely been reported so far. Herein, we report a facile strategy for the synthesis of magnesium silicate hollow nanospheres (MSHNSs) by a classical Stober method and a template based solvothermal process. The as-prepared MSHNSs have an ultrahigh specific surface area of 585.6 m2 g−1, ultrahigh hemoglobin (Hb) protein adsorption capacity (1262 mg g−1) and high doxorubicin (DOX) drug loading capacity (559 mg g−1). Moreover, the as-prepared MSHNS/DOX drug delivery system exhibits sustained and pH-responsive drug release performance. Compared with free DOX, the MSHNS/DOX drug delivery system exhibits higher anticancer activity in vitro, and thus it is promising for applications in anticancer treatment.

Bioactive materials with osteostimulation properties have the potential to promote bone regeneration. We have found that silicate-based biomaterials have the osteostimulation ability for regeneration of large bone defects; however, the corresponding mechanism is unclear. In this study, we set out to elucidate the potential mechanism of silicate-based biomaterials with osteostimulation ability. A model silicate bioceramic, nagelschmidtite (NAGEL, Ca7P2Si2O16), was applied to study their ionic products on the effect of the Bone morphogenic protein (BMP) signaling pathway for osteoblast MC3T3-E1 as NAGEL has been previously shown to have excellent in vitro and in vivo bone-forming activity. BMP signaling, especially BMP2, is involved in bone formation during mammalian development and exhibits versatile regulatory functions in the body. It is found that NAGEL bioceramics significantly enhance the migration and osteoblastic differentiation of MC3T3-E1. mRNA and protein expression of BMP2 is enhanced by NAGEL bioceramics in a dose-dependent manner. Moreover, NAGEL bioceramics activate the Smad-dependent BMP signaling pathway and induce the activation of the BMP downstream cascade (OCN, OPN and Runx2). The accumulation of phosphorylated-Smad1/5 is induced by NAGEL bioceramics in the MC3T3-E1 cell nucleus. It is further found that NAGEL bioceramic-mediated migration, osteoblastic differentiation and the activation of the BMP downstream cascade are significantly downregulated by inhibition of BMP2 activity. Our results suggest that silicate-based NAGEL bioceramics possess excellent in vitro osteostimulation properties and the possible mechanism of silicate-based biomaterials with distinct osteostimulation may be directly related to the activation of the BMP2 signaling pathway of osteoblasts by release of Si-containing bioactive ionic products.

Both osteogenesis and angiogenesis of bioactive materials play the vital role in the regeneration of large skeletal defects. Silicate-based bioceramics have been suggested to possess osteostimulative and angiogenic activity due to the beneficial effect of the released SiO

Simultaneous therapy and regeneration of bone tumor-induced defects still remain to be a significant challenge. Conventional therapy strategy by implanting bone graft materials can regenerate the bone defects after surgery but cannot kill residual tumor cells. In this study, we successfully prepared a 3D-printed β-tricalcium phosphate bioceramic scaffold with surface modification of Fe

The regeneration of periodontal tissues to cure periodontitis remains a medical challenge. Therefore, it is of great importance to develop a novel biomaterial that could induce cementogenesis and osteogenesis in periodontal tissue engineering. Calcium silicate (Ca-Si) based ceramics have been found to be potential bioactive materials due to their osteostimulatory effect. Recently, it is reported that zirconium modified calcium-silicate-based (Ca

Bioactive three-dimensional (3D) scaffolds play a key role in the repair or regeneration of large bone defects. There are many methods to prepare 3D scaffolds, among which the 3D-plotting technique is a promising strategy as the scaffolds prepared by this method possess not only improved mechanical properties and interconnectivity, but also ordered large-pore structure. However, the low cell attachment rate in the interior of the 3D-plotted scaffolds, especially for 3D-plotted bioceramic scaffolds, inhibits the osteogenesis of stem cells in the scaffolds both in vitro and in vivo. The aim of this study is to prepare hierarchically porous composite scaffolds in order to improve the cell attachment, and further stimulate the in vitro and in vivo osteogenesis. We successfully fabricated hierarchically porous bioceramic–silk (BC–silk) composite scaffolds by a combination of the 3D-plotting technique with the freeze-drying method, and further investigated the attachment, proliferation and osteogenic differentiation of bone marrow stromal cells (BMSCs) in the scaffolds as well as the in vivo osteogenesis of the prepared porous scaffolds. The results showed that the hierarchical structure in the composite scaffolds was composed of first-level pores (∼1 mm) of the bioceramic scaffold and second-level pores (∼50–100 μm) of the silk matrix. The prepared BC–silk composite scaffolds possessed excellent apatite-mineralization ability and mechanical properties with compressive strength up to 25 MPa. In addition, hierarchically porous BC–silk scaffolds presented significantly enhanced attachment rate of BMSCs, around 4 times that of pure BC scaffolds without hierarchical pore structures. BC–silk scaffolds with hierarchical pore structures showed distinctively improved cell proliferation, ALP activity and bone-related gene expression as compared to BC scaffolds without hierarchical pore structure. Furthermore, hierarchically porous BC–silk scaffolds significantly enhanced the formation of new bone in vivo as compared to BC scaffolds. Our results suggest that the combination of 3D-plotting with the freeze-drying method is a viable strategy to construct hierarchical pore structures in 3D-plotted scaffolds, and the hierarchical pore structure plays an important role in improving the in vitro and in vivo osteogenesis of 3D-plotted bioceramic scaffolds for bone regeneration application.

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

Correction for ‘Lithium-containing biomaterials inhibit osteoclastogenesis of macrophages in vitro and osteolysis in vivo’ by Chenhao Pan et al., J. Mater. Chem. B, 2018, 6, 8115–8126.

Teeth are important for our life, and enamel, as the outermost layer of the tooth, plays a key role in maintaining the function and health of the tooth. Regeneration of acid eroded enamel is a big challenge due to the lack of living cells in the enamel. Here, we propose a novel way to chemically synthesize the enamel structure by mimicking the interaction of amorphous calcium phosphate (ACP) and acidic proteins during the formation of natural enamel. The process includes the formation of ACP in situ by acid etching and then the formation of a Ca-rich polypeptide-ACP complex on acid etched enamel apatite crystals, the oriented nucleation and growth of apatite nano-crystals along the acid etched enamel apatite crystals, and infiltration of a regenerated enamel apatite structure with dental resin. The synthesized enamel reveals not only excellent mechanical properties, which are highly close to those of original natural enamel, but also reveals high chemical stability against acid erosion. This innovative method may create potential applications of the functional artificial enamel for repairing damaged tooth enamel.

Correction for ‘Strontium-incorporated mesoporous bioactive glass scaffolds stimulating in vitro proliferation and differentiation of bone marrow stromal cells and in vivo regeneration of osteoporotic bone defects’ by Yufeng Zhang et al., J. Mater. Chem. B, 2013, 1, 5711–5722.

A multifunctional Nd-Ca-Si biomaterial is designed for fluorescence thermometry, photothermal therapy, and burn tissue repair., Photothermal therapy (PTT), an emerging tumor treatment technology, has attracted tremendous interest, but excessive heat will cause damage to surrounding healthy tissues. Therefore, in situ temperature monitoring during PTT is of great importance to determine optimal treatment temperature and repair heat-damaged normal tissues. Here, we report the preparation of multifunctional Nd-Ca-Si silicate glasses and glass/alginate composite hydrogels that not only have photothermal property but also emit fluorescence under 808-nm laser irradiation, and its fluorescence intensity is linearly correlated with in situ temperature. With this feature, optimal PTT temperature for effective tumor treatment with minimal normal tissue damage can be obtained. In addition, because of the bioactive silicate components, the composite hydrogel has bioactivity to repair heat damage caused by PTT. This implantable multifunctional material with unique temperature monitoring, photothermal function, and wound healing bioactivity can be used for localized thermal therapy.

Rapid hemostasis and wound healing for emergency trauma is the key to ensure the survival of patients with massive hemorrhage. However, it is still a challenge to develop hemostatic materials with both excellent hemostatic activity and wound healing function. Herein, we propose to fabricate an inorganic hemostatic aerogel mainly based on biocompatible inorganic ultralong hydroxyapatite (HAP) nanowires with polyvinyl alcohol (PVA) as organic binder, and the hemostatic aerogel is prepared by using freeze-drying technology to construct three-dimensional (3D) porous structure, which possesses good plasticity and flexibility. When the content of ultralong HAP nanowires reaches 80 wt%, the W-8HAP-2PVA aerogel (aerogel consists of 80 wt% ultralong HAP nanowires and 20 wt% PVA) exhibits super-hydrophilicity/super-hematophilicity, and its in vitro blood clotting index is only 3.81 ± 0.71 %, which is much lower than that of medical gauze. When applied in hemostasis of rat liver and rabbit femoral artery, the hemostatic time and blood loss amount of the W-8HAP-2PVA aerogel are 26.59 ± 7.46 s, 0.18 ± 0.05 g and 174.00 ± 16.57 s, 2.18 ± 1.56 g, respectively. Benefiting from its excellent hydrophilicity and high porosity structure, W-8HAP-2PVA aerogel can quickly absorb water from blood to concentrate blood cells and platelets and accelerate hemostasis. Notably, it shows good hemocompatibility and cytocompatibility, and is able to promote skin wound healing. Hence, W-8HAP-2PVA aerogel has great potential in rapid hemostasis and wound healing for clinical settings.

Background Induced pluripotent stem cells (iPSCs) exhibit limitless pluripotent plasticity and proliferation capability to provide an abundant cell source for tissue regenerative medicine. Thus, inducing iPSCs toward a specific differentiation direction is an important scientific question. Traditionally, iPSCs have been induced to chondrocytes with the help of some small molecules within 21–36 days. To speed up the differentiation of iPSCs, we supposed to utilize bioactive ceramics to assist chondrogenic-induction process. Methods In this study, we applied ionic products (3.125~12.5 mg/mL) of the lithium-containing bioceramic (Li2Ca4Si4O13, L2C4S4) and individual Li+ (5.78~23.73 mg/L) in the direct chondrogenic differentiation of human iPSCs. Results Compared to pure chondrogenic medium and extracts of tricalcium phosphate (TCP), the extracts of L2C4S4 at a certain concentration range (3.125~12.5 mg/mL) significantly enhanced chondrogenic proteins Type II Collagen (COL II)/Aggrecan/ SRY-Box 9 (SOX9) synthesis and reduced hypertrophic protein type X collagen (COL X)/matrix metallopeptidase 13 (MMP13) production in iPSCs-derived chondrocytes within 14 days, suggesting that these newly generated chondrocytes exhibited favorable chondrocytes characteristics and maintained a low-hypertrophy state. Further studies demonstrated that the individual Li+ ions at the concentration range of 5.78~23.73 mg/L also accelerated the chondrogenic differentiation of iPSCs, indicating that Li+ ions played a pivotal role in chondrogenic differentiation process. Conclusions These findings indicated that lithium-containing bioceramic with bioactive specific ionic components may be used for a promising platform for inducing iPSCs toward chondrogenic differentiation and cartilage regeneration.

In order to further improve the flexural strength of lithium disilicate glass-ceramic, surface strengthening by ion exchange using Rb, Cs nitrates has been studied for the first time. The influences of ion exchange using rubidium and cesium salts on the flexural strength and corrosion resistance have been investigated. It was found that the mechanical properties of the lithium disilicate glass-ceramic could be increased greatly by the ion exchange in rubidium nitrate (RbNO3) salt. After ion exchange for 4 h in RbNO3 salt, the flexural strength and microhardness increased from 169 MPa and 587 kgf mm−2 (5.75 Gpa) of the original lithium disilicate glass-ceramic to 493 MPa and 654 kgf mm−2 (6.4 Gpa), respectively. Moreover, the corrosion resistance of the lithium disilicate glass-ceramic was further improved by ion exchange in rubidium and cesium nitrate salts. Furthermore, the maximum thickness of the ion exchange layer using RbNO3 and CsNO3 was only 4.3 µm and 0.45 µm respectively. Such a thin exchange layer, which will only require very low Rb+, Cs+ ions exchange amount, indicates that the molten salts of RbNO3 and CsNO3 can be reused for many times. So it is suggested that surface strengthening of lithium disilicate glass-ceramic by ion exchange using Rb, Cs nitrates is cost-efficient and very suitable for the actual production and applications.

The creation of a bone substitute with both excellent mechanical strength and bioactivity is still a challenge in bone tissue engineering biomaterials. To this end, inspired by the microstructure of nacre, multilayered graphene oxide/chitosan/calcium silicate (GO/CTS/CS) biomaterials were successfully prepared via a bottom-up assembly approach. The GO/CTS/CS biomaterials emulated the “brick and mortar” layered microstructure via chemical assembly and the multilayered helical cylinder macrostructure. In addition, benefiting from the interface interactions in the layered microstructure as well as the multilayered helical cylinder macrostructure, the GO/CTS/CS biomaterials possessed high flexural strength (137.2 MPa), compressive strength (80.2 MPa), toughness (1.46 MJ/m3), and specific strength (124.7 MPa Mg–1 m–3), which are close to those of cortical bone. Furthermore, because of the bioactive chemical components of GO and CS, the multilayered GO/CTS/CS biomaterials significantly improved osteogenesis and...