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Bioceramics, as one of the typical functional materials, find extensive use in the field of tissue regeneration due to their excellent biocompatibility and bioactivity. However, the high-temperature sintering process and the intrinsic brittleness of bioceramics significantly constrain their manufacturing processes, mechanical performance, and clinical applications. In this context, we have developed an innovative biomass recycling approach to fabricate flexible bioceramics using discarded natural sponge Euplectella aspergillum. By employing a simple, low-energy hydrothermal mineralization process, we transform low-cost natural sponge skeletons into high-value bioceramic scaffolds for tissue regeneration. The naturally derived bioceramic scaffolds exhibit excellent flexibility and machinability and high mechanical strength, far exceeding traditional sintered bioceramics. Furthermore, these scaffolds demonstrate excellent osteogenic and angiogenic capabilities, showcasing significant potential in the repair of flat bones, such as the calvarial and orbital bones. Our work represents a simple and efficient pathway toward the manufacturing of advanced functional bioceramics by repurposing underutilized natural resources.

Organoids, which are 3D multicellular constructs, have garnered significant attention in recent years. Existing organoid culture methods predominantly utilize natural and synthetic polymeric hydrogels. This study explored the potential of a composite hydrogel mainly consisting of calcium silicate (CS) nanowires and methacrylated gelatin (GelMA) as a substrate for organoid formation and functionalization, specifically for intestinal and liver organoids. Furthermore, the research delved into the mechanisms by which CS nanowires promote the structure formation and development of organoids. It was discovered that CS nanowires can influence the stiffness of the hydrogel, thereby regulating the expression of the mechanosensory factor yes-associated protein (YAP). Additionally, the bioactive ions released by CS nanowires in the culture medium could accelerate Wnt/β-catenin signaling, further stimulating organoid development. Moreover, bioactive ions were found to enhance the nutrient absorption and ATP metabolic activity of intestinal organoids. Overall, the CS/GelMA composite hydrogel proves to be a promising substrate for organoid formation and development. This research suggested that inorganic biomaterials hold significant potential in organoid research, offering bioactivities, biosafety, and cost-effectiveness.

Considering the challenge in the treatment of severe breast tumor patients, xonotlite nanowire-containing bioactive scaffolds (Fe3O4-CS-GelMA) were fabricated by the 3D-printing technique for the therapy of injured adipose tissue after surgery. Importantly, benefiting from the excellent magnetothermal performance of Fe3O4microspheres, Fe3O4-CS-GelMA scaffolds could effectively kill tumor cells in vitroand suppress breast cancer in vivounder an alternating magnetic field, and the tumor did not recur in 2 weeks. In addition, attributed to the released bioactive inorganic ions, Fe3O4-CS-GelMA composite scaffolds could effectively promote the expression of adipogenesis-related genes and proteins of adipose-derived stem cells (ADSCs) via the PI3K-AKT signaling pathway in vitro. Furthermore, Fe3O4-CS-GelMA scaffolds with ADSCs could obviously stimulate the formation of adipose in vivo, compared with that of pure GelMA without inorganic components. Therefore, this study offers a promising strategy for the therapy of breast tumors after the surgical excision of breast carcinoma.

Regeneration of severe bone defects remains an enormous challenge in clinic. Developing regenerative scaffolds to directionally guide bone growth is a potential strategy to overcome this hurdle. Conch, an interesting creature widely spreading in ocean, has tough spiral shell that can continuously grow along the spiral direction. Herein, inspired by the physiological features of conches, a conch-like (CL) scaffold based on β-TCP bioceramic material was successfully prepared for guiding directional bone growth viadigital light processing (DLP)-based 3D printing. Benefiting from the spiral structure, the CL scaffolds significantly improved cell adhesion, proliferation and osteogenic differentiation in vitrocompared to the conventional 3D scaffolds. Particularly, the spiral structure in the scaffolds could efficiently induce cells to migrate from the bottom to the top of the scaffolds, which was like “cells climbing stairs”. Furthermore, the capability of guiding directional bone growth for the CL scaffolds was demonstrated by a special half-embedded femoral defects model in rabbits. The new bone tissue could consecutively grow into the protruded part of the scaffolds along the spiral cavities. This work provides a promising strategy to construct biomimetic biomaterials for guiding directional bone tissue growth, which offers a new treatment concept for severe bone defects, and even limb regeneration.

Tendon-bone healing is essential for an effective rotator cuff tendon repair surgery, however, this remains a significant challenge due to the lack of biomaterials with high strength and bioactivity. Inspired by the high-performance exoskeleton of natural organisms, we set out to apply natural fish scale (FS) modified by calcium silicate nanoparticles (CS NPs) as a new biomaterial (CS-FS) to overcome the challenge. Benefit from its “Bouligand” microstructure, such FS-based scaffold maintained excellent tensile strength (125.05 MPa) and toughness (14.16 MJ/m3), which are 1.93 and 2.72 times that of natural tendon respectively, allowing it to well meet the requirements for rotator cuff tendon repair. Additionally, CS-FS showed diverse bioactivities by stimulating the differentiation and phenotypic maintenance of multiple types of cells participated into the composition of tendon-bone junction, (e.g. bone marrow mesenchymal stem cells (BMSCs), chondrocyte, and tendon stem/progenitor cells (TSPCs)). In both rat and rabbit rotator cuff tear (RCT) models, CS-FS played a key role in the tendon-bone interface regeneration and biomechanical function, which may be achieved by activating BMP-2/Smad/Runx2 pathway in BMSCs. Therefore, natural fish scale -based biomaterials are the promising candidate for clinical tendon repair due to their outstanding strength and bioactivity.

Hair loss caused by the abnormal functions of hair follicles in skin can seriously impact the quality of an individual's life. The development of sophisticated skin tissue-engineered constructs is required to enable the function recovery of hair follicles. However, effective hair regrowth in skin substitutes still remains a great challenge. In this study, a 3D multicellular micropattern was successfully fabricated by arranging the hair follicle-related cells orderly distributed in the interval of vascular-cell networks viabioprinting technology. By combining the stable biomimetic micropattern structure and the bio-inducing substrate incorporated with magnesium silicate (MS) nanomaterials, the 3D multicellular micropattern possessed significant follicular potential and angiogenic capacity in vitro. Furthermore, the 3D multicellular micropattern with MS incorporation contributed to efficient hair regrowth during skin tissue regeneration in both immunodeficient mice and androgenetic alopecia (AGA) mice models. Thus, this study proposes a novel 3D micropatterned multicellular system assembling a biomimetic micro-structure and modulating the cell–cell interaction for hair regeneration during skin reconstruction.

To prevent postoperative skin tumor recurrence and repair skin wound, a glucose oxidase (GOx)-loaded manganese silicate hollow nanospheres (MS HNSs)-incorporated alginate hydrogel (G/MS-SA) was constructed for starvation-photothermal therapy and skin tissue regeneration. The MS HNSs showed a photothermal conversion efficiency of 38.5%, and endowed composite hydrogels with satisfactory photothermal effect. Taking advantage of the catalytic activity of Mn ions, the composite hydrogels could decompose hydrogen peroxide (H2O2) into oxygen (O2), which can alleviate the problem of tumor hypoxia microenvironment and endow GOx with an ability to consume glucose in the presence of O2for tumor starvation. Meanwhile, hyperthermia triggered by near infrared (NIR) irradiation could not only accelerate the reaction rate of H2O2decomposition by MS HNSs and glucose consumption by GOx, but also ablate tumor cells. The anti-tumor results showed that synergistic effect of starvation-photothermal therapy led to the highest death rate of tumor cells among all groups, and its anti-tumor effect was obviously improved as compared with that of single photothermal treatment or starvation treatment. Interestingly, the introduction of MS HNSs into hydrogels could distinctly promote the epithelialization of the wound beds by releasing Mn ions as compared with the hydrogels without MS HNSs. It is expected that such a multifunctional platform with starvation-photothermal therapy will be promising for treating tumor-caused skin defects in combination of its regeneration bioactivity in the future.

Osteoporosis is caused by an osteoclast activation mechanism. People suffering from osteoporosis are prone to bone defects. Increasing evidence indicates that scavenging reactive oxygen species (ROS) can inhibit receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclastogenesis and suppress ovariectomy-induced osteoporosis. It is critical to develop biomaterials with antioxidant properties to modulate osteoclast activity for treating osteoporotic bone defects. Previous studies have shown that manganese (Mn) can improve bone regeneration, and Mn supplementation may treat osteoporosis. However, the effect of Mn on osteoclasts and the role of Mn in osteoporotic bone defects remain unclear. In present research, a model bioceramic, Mn-contained β-tricalcium phosphate (Mn-TCP) was prepared by introducing Mn into β-TCP. The introduction of Mn into β-TCP significantly improved the scavenging of oxygen radicals and nitrogen radicals, demonstrating that Mn-TCP bioceramics might have antioxidant properties. The in vitroand in vivofindings revealed that Mn2+ions released from Mn-TCP bioceramics could distinctly inhibit the formation and function of osteoclasts, promote the differentiation of osteoblasts, and accelerate bone regeneration under osteoporotic conditions in vivo. Mechanistically, Mn-TCP bioceramics inhibited osteoclastogenesis and promoted the regeneration of osteoporotic bone defects by scavenging ROS via Nrf2 activation. These results suggest that Mn-containing bioceramics with osteoconductivity, ROS scavenging and bone resorption inhibition abilities may be an ideal biomaterial for the treatment of osteoporotic bone defect.

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.

Tissue regeneration is a complicated process that relies on the coordinated effort of the nervous, vascular and immune systems. While the nervous system plays a crucial role in tissue regeneration, current tissue engineering approaches mainly focus on restoring the function of injury-related cells, neglecting the guidance provided by nerves. This has led to unsatisfactory therapeutic outcomes. Herein, we propose a new generation of engineered neural constructs from the perspective of neural induction, which offers a versatile platform for promoting multiple tissue regeneration. Specifically, neural constructs consist of inorganic biomaterials and neural stem cells (NSCs), where the inorganic biomaterials endows NSCs with enhanced biological activities including proliferation and neural differentiation. Through animal experiments, we show the effectiveness of neural constructs in repairing central nervous system injuries with function recovery. More importantly, neural constructs also stimulate osteogenesis, angiogenesis and neuromuscular junction formation, thus promoting the regeneration of bone and skeletal muscle, exhibiting its versatile therapeutic performance. These findings suggest that the inorganic-biomaterial/NSC-based neural platform represents a promising avenue for inducing the regeneration and function recovery of varying tissues and organs.A new concept that developing an engineered inorganic biomaterials/neural stem cells (NSCs)-based neural platform to resolve the dilemma of multiple tissue regeneration with functions recovery in regenerative medicine is proposed.

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 vivoresults 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.

The development of an engineered non-contact multicellular coculture model that can mimic the in vivocell microenvironment of human tissues remains challenging. In this study, we successfully fabricated a cell-container-like scaffold composed of β-tricalcium phosphate/hydroxyapatite (β-TCP/HA) bioceramic that contains four different pore structures, including triangles, squares, parallelograms, and rectangles, by means of three-dimensional (3D) printing technology. These scaffolds can be used to simultaneously culture four types of cells in a non-contact way. An engineered 3D coculture model composed of human bone-marrow-derived mesenchymal stem cells (HBMSCs), human umbilical vein endothelial cells (HUVECs), human umbilical vein smooth muscle cells (HUVSMCs), and human dermal fibroblasts (HDFs) with a spatially controlled distribution was constructed to investigate the individual or synergistic effects of these cells in osteogenesis and angiogenesis. The results showed that three or four kinds of cells cocultured in 3D cell containers exhibited a higher cell proliferation rate in comparison with that of a single cell type. Detailed studies into the cell–cell interactions between HBMSCs and HUVECs revealed that the 3D cell containers with four separate spatial structures enhanced the angiogenesis and osteogenesis of cells by amplifying the paracrine effect of the cocultured cells. Furthermore, the establishment of multicellular non-contact systems including three types of cells and four types of cells, respectively, cocultured in 3D cell containers demonstrated obvious advantages in enhancing osteogenic and angiogenic differentiation in comparison with monoculture modes and two-cell coculture modes. This study offers a new direction for developing a scaffold-based multicellular non-contact coculture system for tissue regeneration.

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.

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.

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.

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.

Diabetic wound is one of the chronic wounds that is difficult to heal, and effective treatment of it still confronts a great challenge. Monitoring the variation of diabetic wound microenvironment (such as hydrogen peroxide (H2O2)) can understand the wound state and guide the wound management. Herein, a multifunctional hydrogel with the abilities of monitoring the H2O2concentration, alleviating oxidative stress and promoting wound healing is developed, which is prepared by encapsulating manganese‐containing bioactive glass (MnBG) and CePO4:Tb in biocompatible gelatin methacryloyl (GelMA) hydrogel (CPT‐MnBG‐Gel). On the one hand, the H2O2‐dependent fluorescence quenching effect of the CePO4:Tb contributes to visible monitoring of the H2O2concentration of wounds via smartphone imaging, and the CPT‐MnBG‐Gel hydrogel can effectively monitor the H2O2level of 10.35–200 µmol L−1. On the other hand, MnBG can alleviate oxidative stress and promote the proliferation, migration and differentiation of fibroblasts and endothelial cells in vitro owing to the bioactive Mn and Si ions, and in vivo evaluation also demonstrates that the CPT‐MnBG‐Gel hydrogels can effectively accelerate wound healing. Hence, such multifunctional hydrogel is promising for diabetic wound management and accelerating wound healing. A H2O2‐responsive smart hydrogel (CPT‐MnBG‐Gel) consists of GelMA hydrogel, MnBG, and CePO4:Tb particles is successfully prepared, which can alleviate oxidative stress and promote proliferation, migration, and differentiation of fibroblasts and endothelial cells. Such CPT‐MnBG‐Gel hydrogel can be applied as a multifunctional dressing for diabetic wound management and accelerating wound healing.

Osteochondral regeneration involves the highly challenging and complex reconstruction of cartilage and subchondral bone. Silicon (Si) ions play a crucial role in bone development. Current research on Si ions mainly focuses on bone repair, by using silicate bioceramics with complex ion compositions. However, it is unclear whether the Si ions have important effect on cartilage regeneration. Developing a scaffold that solely releases Si ions to simultaneously promote subchondral bone repair and stimulate cartilage regeneration is critically important. Diatomite (DE) is a natural diatomaceous sediment that can stably release Si ions, known for its abundant availability, low cost, and environmental friendliness. Herein, a hierarchical osteochondral repair scaffold is uniquely designed by incorporating gradient DE into GelMA hydrogel. The adding DE microparticles provides a specific Si source for controlled Si ions release, which not only promotes osteogenic differentiation of rBMSCs (rabbit bone marrow mesenchymal stem cells) but also enhances proliferation and maturation of chondrocytes. Moreover, DE-incorporated hierarchical scaffolds significantly promoted the regeneration of cartilage and subchondral bone. The study suggests the significant role of Si ions in promoting cartilage regeneration and solidifies their foundational role in enhancing bone repair. Furthermore, it offers an economic and eco-friendly strategy for developing high value-added osteochondral regenerative bioscaffolds from low-value ocean natural materials.

Silicon (Si)‐based biomaterials are widely applied for bone regeneration. However, the underlying mechanisms of the materials function remain largely unknown. T lymphocyte‐mediated adaptive immune response plays a vital role in the process of bone regeneration. In the current study, mesoporous silica (MS) is used as a model material of Si‐based biomaterials. It shows that the supernatant of CD4+T lymphocytes pretreated with MS extract significantly promotes the vascularized bone regeneration. The potential mechanism is closely related to the fact that MS extract can reduce the expression of regulatory factor X‐1 (RFX‐1) in CD4+T lymphocytes. This may result in the overexpression of interleukin‐17A (IL‐17A) by boosting histone H3 acetylation and lowering DNA methylation and H3K9 trimethylation. Importantly, the in vivo experiments further reveal that MS particles significantly enhance 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. This study suggests that modulation of the adaptive immune response of T lymphocytes by silicate‐based biomaterials plays an important role for bone regeneration. The extract of mesoporous silica (MS) reduces the expression of regulatory factor X‐1 (RFX‐1) in CD4+T lymphocytes, which results in the overexpression of interleukin‐17A (IL‐17A) and enhances in vivo bone regeneration. These findings suggest that modulation of the adaptive immune response of T lymphocytes by silicate‐based biomaterials plays an important role for bone regeneration.

Grape-seed extracts contain rich flavonoids with oligomeric proanthocyanidins (OPC). In this study, OPC containing hydrogel scaffolds can function as a natural photothermal agent for melanoma therapy and bioactive biomaterial for wound healing. Inspired by grape-seed extracts, OPC were explored as a photothermal agent and endowed the hydrogel scaffolds with excellent and controlled photothermal ability. The rheological property of the hydrogel scaffolds responded to irradiation time of near infrared (NIR) laser, and OPC contents. The compressive mechanical property of the hydrogel scaffolds was well modulated by NIR laser irradiation with different impact durations. The controlled high temperature induced by OPC-containing hydrogel scaffolds under NIR laser irradiation could effectively kill melanoma cells and suppress tumor growth. In addition, OPC-containing hydrogel scaffolds supported the proliferation and migration of human dermal fibroblasts and human umbilical vein endothelial cells, as well as obviously promoted angiogenesis and skin regeneration in both tumor-caused and chronic wounds. Therefore, OPC-containing hydrogel scaffolds possessed controlled photothermal, rheological, and compressive mechanical properties under NIR laser stimuli, as well as excellent biocompatibility and bioactivity for melanoma therapy and wound healing.

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.

Current challenges in cutaneous tumor therapy are healing the skin wounds resulting from surgical resection and eliminating possible residual tumor cells to prevent recurrence. To address this issue, bifunctional biomaterials equipped with effective tumor therapeutic capacity for skin cancers and simultaneous tissue regenerative ability for wound closure are highly recommended. Herein, we report an injectable thermosensitive hydrogel (named BT-CTS thermogel) with the integration of nanosized black titania (B-TiO2–x, ∼50 nm) nanoparticles into a chitosan (CTS) matrix. The B-TiO2–xnanocrystal exhibits a crystalline/amorphous core–shell structure with abundant oxygen vacancies, which endows the BT-CTS thermogels with simultaneous photothermal therapy (PTT) and photodynamic therapy (PDT) effects under single-wavelength near-infrared laser irradiation, leading to an excellent therapeutic effect on skin tumors in vitro and in vivo. Moreover, the BT-CTS thermogel not only supports the adhesion, proliferation, and migration of normal skin cells but also facilitates skin tissue regeneration in a murine chronic wound model. Therefore, such BT-CTS thermogels with easy injectability, excellent thermostability, and simultaneous PTT and PDT efficacy as well as tissue regenerative activity offers a promising pathway for the healing of cutaneous tumor-induced wounds.

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–1m–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 angiogenesis in vitro. Moreover, the multilayered GO/CTS/CS biomaterials showed enhanced in vivobone-forming ability due to the contributions of bioactive chemical components and the multilayered helical cylinder macrostructure. This work not only provides a biomaterial with excellent mechanical strength and bioactivity but also offers a strategy for fabrication of high-performance biomaterials based on bioinspired chemistry and engineering.

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-CaSiO3composite 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 CaSiO3in 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-CaSiO3composite 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 vitroand in vivo; Thirdly, the presence of CaSiO3in 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 treatment of melanoma requires complete removal of tumor cells and simultaneous tissue regeneration of tumor-initiated cutaneous defects. Herein, copper silicate hollow microspheres (CSO HMSs)-incorporated bioactive scaffolds were designed for chemo-photothermal therapy of skin cancers and regeneration of skin tissue. CSO HMSs were synthesized with interior hollow and external nanoneedle microstructure, showing excellent drug-loading capacity and photothermal effects. With incorporation of drug-loaded CSO HMSs into the electrospun scaffolds, the composite scaffolds exhibited excellent photothermal effects and controlled NIR-triggered drug release, leading to distinctly synergistic chemo-photothermal therapy of skin cancer both in vitroand in vivo. Furthermore, such CSO HMSs-incorporated scaffolds could promote proliferation and attachment of normal skin cells and accelerate skin tissue healing in tumor-bearing and diabetic mice. Taken together, CSO HMSs-incorporated scaffolds may be used for complete eradication of the remaining tumor cells after surgery and simultaneous tissue healing, which offers an effective strategy for therapy and regeneration of tumor-initiated tissue defects.

Surgical excision of skin cancers can hardly remove the tumor tissues completely and simultaneously result in cutaneous defects. To avoid tumor recurrence and heal the tumor-induced wounds, we designed a tissue engineering membrane possessing bifunctions of tumor therapy and skin tissue regeneration. The micropatterned nanocomposite membrane was successfully fabricated by incorporating Cu2S nanoflowers into biopolymer fibers viaa modified electrospinning method. With uniformly embedded Cu2S nanoparticles, the membranes exhibited excellent and controllable photothermal performance under near-infrared irradiation, which resulted in high mortality (>90%) of skin tumor cells and effectively inhibited tumor growth in mice. Moreover, the membranes supported the adhesion, proliferation, and migration of skin cells as well as significantly stimulated angiogenesis and healed full-thickness skin defects in vivo. This proof-of-concept study offers a facile and reliable strategy for localized skin tumor therapy and tissue regeneration using bifunctional tissue engineering biomaterials, showing great promise for tumor-induced wound healing applications.

For regeneration of highly vascularized and innervated tissues, like bone, simultaneous ingrowth of blood vessels and nerves is essential but largely neglected. To address this issue, a “pre‐angiogenic” cell‐laden scaffold with durable angiogenic functions is prepared according to the bioactivities of silicate bioceramics and the instructive effects of vascular cells on neurogenesis and bone repair. Compared with traditional cell‐free scaffolds, the prepared cell‐laden scaffolds printed with active cells and bioactive inks can support long‐term cell survival and growth for three weeks. The long‐lived scaffolds exhibited durable angiogenic capability both in vitro and in vivo. The pre‐angiogenic scaffolds can induce the neurogenetic differentiation of neural cells and the osteogenic differentiation of mesenchymal stem cells by the synergistic effects of released bioactive ions and the ability of vascular cells to attract neurons. The enhanced bone regeneration with both vascularization and innervation is attributed to these physiological functions of the pre‐angiogenic cell‐laden scaffolds, which is defined as “vascular‐innervated” bone regeneration. It is suggested that the concept of “vascular‐innervated scaffolds” may represent the future direction of biomaterials for complex tissue/organ regeneration. The pre‐angiogenic cell‐laden scaffolds are 3D bioprinted with Li‐Mg‐Si (LMS) bioceramics‐based bioinks containing vascular endothelial cells. The cell‐laden scaffolds possessed the ability of modulating innervation and osteogenesis while holding long‐lived angiogenic functions. When implanted into bone defects, the cell‐laden scaffolds can promote ingrowth of blood vessels and nerve fibers and enhance bone formation, leading to the high efficiency of vascular‐innervated bone regeneration.

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 (Ca3SiO5and 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 controllable 3D structure at room temperature. The scaffolds were loaded with two model drugs and showed a loading location controllable drug-release profile. In addition, we developed a surface modification process to create controllable nanotopography on the surface of pore wall of the scaffolds, which showed activity to enhance rat bone-marrow stem cells (rBMSCs) attachment, spreading, and ALP activities. The in vivo experiments revealed that the 3D-printed C3S bone cement scaffolds with nanoneedle-structured surfaces significantly improved bone regeneration, as compared to pure C3S bone cement scaffolds, suggesting that 3D-printed C3S bone cement scaffolds with controllable nanotopography surface are bioactive implantable biomaterials for bone repair.

The repair of damaged cartilage still remains a great challenge in clinic. It is demonstrated that bone marrow stromal cells (BMSCs)‐chondrocytes communication is of great significance for cartilage repair. Moreover, BMSCs have been confirmed to enhance biological function of chondrocytes via exosome‐mediated paracrine pathway. Lithium‐containing scaffolds have been reported to effectively promote cartilage regeneration; however, whether lithium‐containing biomaterial could facilitate cartilage regeneration through regulating BMSCs‐derived exosomes has not been illustrated. In the study, the model lithium‐substituted bioglass ceramic (Li‐BGC) is selected and regulatory effects of BMSCs‐derived exosomes after Li‐BGC treatment (Li‐BGC‐Exo) are systemically evaluated. The data reveal that Li‐BGC‐Exo notably promotes chondrogenesis, which attributes to the upregulated exosomal miR‐455‐3p transfer, consequently leads to suppression of histone deacetylase 2 (HDAC2) and enhanced histone H3 acetylation in chondrocytes. Notably, BMSCs‐derived exosomes after LiCl treatment (LiCl‐Exo) exhibits the similar regulatory effect with Li‐BGC‐Exo, indicating that the pro‐chondrogenesis capability of them is mainly owing to the lithium ions. Furthermore, the in vivo study proves that LiCl‐Exo remarkably facilitates cartilage regeneration. The research may provide novel possibility for the intrinsic mechanism of chondrogenesis trigged by lithium‐containing biomaterials, and suggests that application of lithium‐containing scaffolds may be a promising strategy for cartilage regeneration. This study demonstrates that lithium‐substituted bioglass ceramic treatment upregulates bone marrow stromal cells‐derived exosomal miR‐455‐3p, which results in suppression of histone deacetylase 2 (HDAC2) and enhanced histone H3 acetylation in chondrocytes, thereby facilitating chondrogenesis. It may provide novel insight for mechanisms underlying Li‐containing biomaterials‐mediated chondrogenesis, and suggest that application of Li‐containing scaffolds may be a promising strategy for cartilage regeneration.

Current conventional treatments for malignant melanoma still face limitations, especially low therapeutic efficacy and serious side effects, and more effective strategies are urgently needed to develop them. Delivering biocatalysts into tumors to efficiently trigger in situ cascade reactions has shown huge potential in producing more therapeutic species or generating stronger tumoricidal effects for augmented tumor therapy. Recently, ultrathin 2D metal–organic framework (MOF) nanosheets have acquired great interest in biocatalysis owing to their large surface areas and abundant accessible active catalytic sites. Herein, an enhanced catalytic therapeutic strategy against melanoma is developed by biocompatible microneedle (MN)‐assisted transdermal delivery of a 2D bimetallic MOF nanosheet‐based cascade biocatalyst (Cu‐TCPP(Fe)@GOD). Profiting from the constructed dissolving MN system, the loaded Cu‐TCPP(Fe)@GOD hybrid nanosheets can be accurately delivered into the melanoma sites through skin barriers, and subsequently, trigger the specific cascade catalytic reactions in response to the acidic tumor microenvironment to effectively generate highly toxic hydroxyl radical (•OH) and deplete glucose nutrient for inducing the death of melanoma cells. The ultimate results prove the high melanoma inhibition effect and biosafety of such therapeutic modality, exhibiting a new and promising strategy to conquer malignant melanoma. A transdermal microneedle system loaded with a 2D bimetallic metal–organic framework nanosheet‐based cascade biocatalyst is developed for enhanced catalytic therapy of malignant melanoma by triggering the in situ cascade catalytic reactions within the tumor microenvironments to effectively generate highly toxic hydroxyl radical (•OH) and deplete glucose nutrient.

The emergence of nanosheet materials like graphene and phosphorene, which are created by breaking the interlayer van der Waals force, has revolutionized multiple fields. Layered inorganic materials are ubiquitous in materials like bioceramics, semiconductors, superconductors, etc. However, the strong interlayer covalent or ionic bonding in these crystals makes it difficult to fabricate nanosheets from them. In this study, we present a simple technique to produce nanosheets from layered crystals by selectively exfoliating their interlayer metal atoms using the metal-chelation reaction. As a proof of concept, we successfully produced bioceramic nanosheets (BCene) by extracting Ca layers from Akermanite (AKT). The 3D-printed BCene scaffolds exhibited superior mechanical strength and in vitrobioactivity compared to the scaffolds made from AKT nanopowders. Our findings demonstrate the outstanding potential of BCene nanosheets in tissue engineering. Additionally, the selective demetallization technique for nanosheet production could be applied to other inorganic layered crystals to optimize their performance.

Tissue engineering strategy that combine biomaterials with living cells has shown special advantages in tissue regeneration and promoted the development of regenerative medicine. In particular, the rising of 3D printing technology further enriched the structural design and composition of tissue engineering scaffolds, which also provided convenience for cell loading and cell delivery of living cells. In this review, two types of cell-delivery scaffolds for tissue regeneration, including 3D printed scaffolds with subsequent cell-seeding and 3D cells bioprinted scaffolds, are mainly reviewed. We devote a major part to present and discuss the recent advances of two 3D printed cell-delivery scaffolds in regeneration of various tissues, involving bone, cartilage, skin tissues etc. Although two types of 3D printed cell-delivery scaffolds have some shortcomings, they do have generally facilitated the exploration of tissue engineering scaffolds in multiple tissue regeneration. It is expected that 3D printed cell-delivery scaffolds will be further explored in function mechanism of seeding cells in vivo, precise mimicking of complex tissues and even organ reconstruction under the cooperation of multiple fields in future.

The positive regulation of bone-forming osteoblast activity and the negative feedback regulation of osteoclastic activity are equally important in strategies to achieve successful alveolar bone regeneration. Here, a molybdenum (Mo)-containing bioactive glass ceramic scaffold with solid-strut-packed structures (Mo-scaffold) was printed, and its ability to regulate pro-osteogenic and anti-osteoclastogenic cellular responses was evaluated in vitro and in vivo. We found that extracts derived from Mo-scaffold (Mo-extracts) strongly stimulated osteogenic differentiation of bone marrow mesenchymal stem cells and inhibited differentiation of osteoclast progenitors. The identified comodulatory effect was further demonstrated to arise from Mo ions in the Mo-extract, wherein Mo ions suppressed osteoclastic differentiation by scavenging reactive oxygen species (ROS) and inhibiting mitochondrial biogenesis in osteoclasts. Consistent with the in vitro findings, the Mo-scaffold was found to significantly promote osteoblast-mediated bone formation and inhibit osteoclast-mediated bone resorption throughout the bone healing process, leading to enhanced bone regeneration. In combination with our previous finding that Mo ions participate in material-mediated immunomodulation, this study offers the new insight that Mo ions facilitate bone repair by comodulating the balance between bone formation and resorption. Our findings suggest that Mo ions are multifunctional cellular modulators that can potentially be used in biomaterial design and bone tissue engineering.

Bone tissue engineering offers a possible strategy for regenerating large bone defects, in which how to design beneficial scaffolds for accelerating bone formation remains significantly challenging. Europium, as an important rare earth element, has been used as a solid-state lighting material. However, there are few reports on whether Eu can be used for labeling bone tissue engineering scaffolds, and its biological effect on bone cells and bone tissue regeneration is unknown. In this study, we incorporated Eu into mesoporous bioactive glass (Eu-MBG) scaffolds by an in situ cotemplate method to achieve a bifunctional biomaterial with biolabeling and bone regeneration. The prepared Eu-MBG scaffolds have highly interconnective large pores (300–500 μm), a high specific surface area (140–290 m2/g), and well-ordered mesopores (5 nm) as well as uniformly distributed Eu. The incorporation of 2–5 mol % Eu into MBG scaffolds gives them a luminescent property. The in vitro degradation of Eu-MBG scaffolds has a functional effect on the change of the luminescence intensity. In addition, Eu-MBG can be used for labeling bone marrow stromal cells (BMSCs) in vitro and still presents a distinct luminescence signal in deep bone tissues in vivo to label new bone tissue via release of Eu ions. Furthermore, the incorporation of different contents of Eu (1, 2, and 5 mol %) into MBG scaffolds significantly enhances the osteogenic gene expression of BMSCs in the scaffolds. The Eu- and Si-containing ionic products released from Eu-MBG scaffolds distinctly promote the osteogenic differentiation of BMSCs. Critically sized femur defects in ovariectomized (OVX) rats are created to simulate an osteoporotic phenotype. The results show that Eu-MBG scaffolds significantly stimulate new bone formation in osteoporotic bone defects when compared to MBG scaffolds alone and Eu may be involved in the acceleration of bone regeneration in OVX rats. Our study for the first time reports that the incorporation of the rare earth element Eu into bioscaffolds has the ability to accelerate bone regeneration in vivo, and thus, the prepared Eu-MBG scaffolds possess bifunctional properties with biolabeling and bone regeneration.

Gingival recession is a common clinical problem that results in esthetic deficiencies and poor plaque control and predominantly occurs in aged patients. In order to restore the cervical region, ideal biomaterials should possess the ability to stimulate proliferation and osteogenesis/cementogenesis of human gingival fibroblasts (HGF) and have a strong antibiofilm effect. The aim of the present study was to investigate the interactions of HGF and oral multispecies biofilms with Ca, Mg and Si-containing bredigite (BRT, Ca7MgSi4O16) bioceramics. BRT extract induced osteogenic/cementogenic differentiation of HGF and its inhibition of plaque biofilm formation were systematically studied. BRT extract in concentrations lower than <200 mg mL−1presented high biocompatibility to HGF cells in 3 days. Ion extracts from BRT also stimulated a series of bone-related gene and protein expressions in HGF cells. Furthermore, BRT extract significantly inhibited oral multispecies plaque biofilm growth on its surface and contributed to over 30% bacterial cell death without additional antibacterial agents in two weeks. A planktonic killing test showed that BRT suppressed 98% plaque bacterial growth compared to blank control in 3 days. The results also revealed that BRT extract has an osteostimulation effect on HGF. The suppression effect on plaque biofilms suggested that BRT might be used as a bioactive material for cervical restoration and that the synergistic effect of bioactive ions, such as Ca, Mg and Si ions, played an important role in the design and construction of bifunctional biomaterials in combination with tissue regeneration and antibiofilm activity.

The aim of this study was to achieve on-demand controlled drug release from the dual-drug-loaded poly(lactic-co-glycolic acid)/mesoporous silica nanoparticles electrospun composite fibers by the application of ultrasound irradiation. Two drugs were loaded in different part of the composite fibrous materials, and it was found that ultrasound as an external stimulus was able to control release of drugs due to both its thermal effect and non-thermal effect. With the selective irradiation of ultrasound, the drug carrier enabled to realize controlled release, and because of different location in fibers and sensitivity of two different kinds of drugs to ultrasound irradiation, the release rate of two drugs was different. These results indicated that ultrasound irradiation was a facile method to realize the on-demand controlled release of two drugs from the electrospun fibers.

Three-dimensional printing technologies have shown distinct advantages to create porous scaffolds with designed macropores for application in bone tissue engineering. However, until now, 3D-printed bioceramic scaffolds only possessing a single type of macropore have been reported. Generally, those scaffolds with a single type of macropore have relatively low porosity and pore surfaces, limited delivery of oxygen and nutrition to surviving cells, and new bone tissue formation in the center of the scaffolds. Therefore, in this work, we present a useful and facile method for preparing hollow-struts-packed (HSP) bioceramic scaffolds with designed macropores and multioriented hollow channels via a modified coaxial 3D printing strategy. The prepared HSP scaffolds combined high porosity and surface area with impressive mechanical strength. The unique hollow-struts structures of bioceramic scaffolds significantly improved cell attachment and proliferation and further promoted formation of new bone tissue in the center of the scaffolds, indicating that HSP ceramic scaffolds can be used for regeneration of large bone defects. In addition, the strategy can be used to prepare other HSP ceramic scaffolds, indicating a universal application for tissue engineering, mechanical engineering, catalysis, and environmental materials.

The challenge for treatment of severe cutaneous wound poses an urgent clinical need for the development of biomaterials to promote skin regeneration. In the past few decades, introduction of inorganic components into material system has become a promising strategy for improving performances of biomaterials in the process of tissue repair. In this review, we provide a current overview of the development of bioactive inorganic particles‐based biomaterials used for skin tissue engineering. We highlight the three stages in the evolution of the bioactive inorganic biomaterials applied to wound management, including single inorganic materials, inorganic/organic composite materials, and inorganic particles‐based cell‐encapsulated living systems. At every stage, the primary types of bioactive inorganic biomaterials are described, followed by citation of the related representative studies completed in recent years. Then we offer a brief exposition of typical approaches to construct the composite material systems with incorporation of inorganic components for wound healing. Finally, the conclusions and future directions are suggested for the development of novel bioactive inorganic particles‐based biomaterials in the field of skin regeneration. The inorganic biomaterials for wound healing have aroused widespread concern in the field of tissue engineering. The three main forms of application of inorganic particles for skin repair are summarized based on the complexity of material system. The representative types of inorganic biomaterials and fabrication technology of wound dressings are presented.

The development of an artificial graft with distinct osteogenetic activity to enhance osseointegration and to induce the formation of biomimetic tissue structure for ligament reconstruction remains a significant challenge. Inspired by mussels, biomimetic calcium phosphate apatite/polydopamine hybridized–polyethylene terephthalate (APA/PDA–PET) grafts were successfully prepared. The efficacy and mechanism of APA/PDA–PET grafts to induce osseointegration were systematically investigated. The results from the in vitrostudy indicated that the prepared APA/PDA–PET grafts support the attachment of bone marrow stromal cells (BMSCs) and stimulate the proliferation and osteogenic/angiogenic differentiation of BMSCs via activation of the PKC/p-ERK1/2 signaling pathway. In vivo, histological and radiological results further demonstrate that the APA/PDA–PET grafts significantly improve osseointegration by inducing the formation of new bone tissue and the fibrocartilage transitional zone compared with pure PET grafts. In addition, the pull-out strength of the APA/PDA–PET grafts is significantly higher than that of the pure PET grafts 12 weeks after surgery. These results suggest that this mussel-inspired biomimetic method is an effective strategy for modifying artificial grafts, and the prepared APA/PDA–PET grafts, which possess a beneficial interface, can significantly improve in vivoosseointegration for ligament reconstruction via the synergistic effect of polydopamine and apatite.

Composite scaffolds, especially polymer/hydroxyapatite (HAP) composite scaffolds with predesigned structures, are promising materials for bone tissue engineering. Various methods including direct mixing of HAP powder with polymers or incubating polymer scaffolds in simulated body fluid for preparing polymer/HAP composite scaffolds are either uncontrolled or require long times of incubation. In this work, alginate/nano-HAP composite scaffolds with designed pore parameters and core/shell structures were fabricated using 3D plotting technique and in situ mineralization under mild conditions (at room temperature and without the use of any organic solvents). Light microscopy, scanning electron microscopy, microcomputer tomography, X-ray diffraction, and Fourier transform infrared spectroscopy were applied to characterize the fabricated scaffolds. Mechanical properties and protein delivery of the scaffolds were evaluated, as well as the cell response to the scaffolds by culturing human bone-marrow-derived mesenchymal stem cells (hBMSC). The obtained data indicate that this method is suitable to fabricate alginate/nano-HAP composite scaffolds with a layer of nano-HAP, coating the surface of the alginate strands homogeneously and completely. The surface mineralization enhanced the mechanical properties and improved the cell attachment and spreading, as well as supported sustaining protein release, compared to pure alginate scaffolds without nano-HAP shell layer. The results demonstrated that the method provides an interesting option for bone tissue engineering application.

The construction of hierarchical porous structure in biomaterials is of great significance for improving nutrient transport and biological performance. However, it is still challenging to design porous bone substitutes with high strength and biological properties, which limits their clinical applications in load‐bearing bone regeneration. Herein, based on hierarchical porous structure of renewable bamboo, the mineralized calcium phosphate/bamboo composite scaffolds with high strength and excellent transport performance are successfully prepared in combination of biotemplated approach and biomimetic mineralization. The mineralized biomaterials have simultaneously achieved high mechanical strength and low modulus, similar to those of cortical bone. Furthermore, the mineralized biomaterials exhibit good liquid transport capacity and can transport cells along anti‐gravity direction. Based on density functional theory (DFT) calculations, the mineralized calcium phosphate reveals the optimal H2O adsorption energy (−0.651 eV) and low diffusion energy barrier (0.743 eV), which is conducive to enhance hydrophilicity and liquid transport performance. Moreover, owing to the synergistic effect of the porous structure of biotemplate and bioactive mineralized components, the mineralized biomaterials possess enhanced bone integration and osteoconduction properties. The present study shed light on deeper understanding of mineralized biosourced materials, offering a strategy of combining green chemistry with tissue engineering to prepare eco‐friendly biomaterials. Calcium phosphate‐mineralized biomaterials with high strength are successfully prepared based on renewable bamboo biotemplates. The mineralized biomaterials have achieved high mechanical strength and low modulus simultaneously, similar to cortical bone. Moreover, the mineralized biomaterials possess good cell transport capacity and enhanced bioactivity. Such biosourced biomaterials are believed to provide effective approach for the interconnection of green chemistry and tissue engineering.

The application of inorganic biomaterials in regenerative medicine is increasingly expanded. Taking advantages of attractive properties of the inorganic biomaterials, sorts of functional bioinks have been developed based on inorganic biomaterials and were applied to construct inorganic/organic/cell‐laden systems for tissue regeneration via 3D bioprinting technology. In this review, we aim to summarize the existing inorganic biomaterials‐based bioinks (referred to as “inorganic‐bioinks”) for 3D bioprinting regenerative scaffolds. We introduce the recently developed inorganic‐bioinks from the perspective of the function of bioinks, and especially highlight the incorporation of inorganic biomaterials improving the printability, mechanical strength, and bioactivity of the bioinks for different tissue regeneration. Subsequently, the current applications of the inorganic‐bioinks in constructing 3D cell‐laden scaffolds for tissue regeneration are presented. Finally, challenges and prospects for the inorganic biomaterials‐based bioprinting strategy are discussed. Taking advantages of attractive properties of the inorganic biomaterials, sorts of functional bioinks have been developed based on inorganic biomaterials and were applied to construct inorganic/organic/cell‐laden systems for tissue regeneration via 3D bioprinting technology. In this review, the authors aim to summarize the existing inorganic biomaterials‐based bioinks (referred to as “inorganic‐bioinks”) for 3D bioprinting regenerative scaffolds.

The diversity of phyllotaxis, such as different blade intervals and divergence angles, is the optimal design for matter exchange and information transfer between plants and external environment, which offers beneficial solutions for designing functional materials. Herein, inspired by the phyllotaxis of plants, a tree-like bioceramic (TLB) scaffold was designed as an integrated three-dimensional platform for multicellular delivery and multiple tissue interactions. The leaf blades of the scaffolds sufficiently supported the adhesion, proliferation, and the osteogenic and neurogenic differentiation of mesenchymal stem cells-Schwann cells coculture system. Interestingly, the gradient surface structure of the leaf blades promoted the proliferation and neurogenic differentiation of the coculture system in a thickness-dependent manner. In addition, the tree-like scaffolds with mesenchymal stem cells-Schwann cells coculture exhibited desirable bone regeneration and remarkable nerve regeneration in vivo. The study provides a promising strategy for preparing biomimetic materials with hierarchical structure and multifunctions for innervated bone tissue engineering. To the best of our knowledge, this is the first report of innervated bone regeneration by using a bioceramic scaffold.

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, Zn2SiO4(ZS) nanoparticles‐incorporated bioactive nanofibrous scaffolds are designed for innervated and vascularized skin burn wound healing. ZS nanoparticles with spindle‐like morphology are synthesized via a facile hydrothermal method. The incorporation of ZS nanoparticles endows the scaffolds with excellent angiogenic and neurogenic activities in vitro. Additionally, in vivo results show that the ZS nanoparticles‐incorporated scaffolds have favorable re‐epithelialization, innervation, and vascularization abilities through local release of bioactive Zn and Si ions from ZS nanoparticles, leading to rapid wound healing featuring with newly formed blood vessels and nerve fibers. Taken together, this study suggests that the spindle‐like ZS nanoparticles are useful bioactive agents for stimulating vascularization and innervation of functional skin repair. The bioactive inorganic nanoparticles may be used for multifunctional tissue regeneration. Spindle‐like zinc silicate nanoparticles are synthesized via hydrothermal method and then incorporated into nanofibrous scaffolds to serve as bioactive factors. Due to the sustained release of bioactive Zn and Si ions, zinc silicate nanoparticles‐based multifunctional scaffolds can not only accelerate the healing process of deep second‐degree burn wounds but also reconstruct the damaged neurovascular networks.

Ideal coating materials for implants should be able to induce excellent osseointegration, which requires several important parameters, such as good bonding strength, limited inflammatory reaction, and balanced osteoclastogenesis and osteogenesis, to gain well-functioning coated implants with long-term life span after implantation. Bioactive elements, like Sr, Mg, and Si, have been found to play important roles in regulating the biological responses. It is of great interest to combine bioactive elements for developing bioactive coatings on Ti-6Al-4 V orthopedic implants to elicit multidirectional effects on the osseointegration. In this study, Sr-, Mg-, and Si-containing bioactive Sr2MgSi2O7(SMS) ceramic coatings on Ti-6Al-4 V were successfully prepared by the plasma-spray coating method. The prepared SMS coatings have significantly higher bonding strength (∼37 MPa) than conventional pure hydroxyapatite (HA) coatings (mostly in the range of 15–25 MPa). It was also found that the prepared SMS coatings switch the macrophage phenotype into M2 extreme, inhibiting the inflammatory reaction via the inhibition of Wnt5A/Ca2+and Toll-like receptor (TLR) pathways of macrophages. In addition, the osteoclastic activities were also inhibited by SMS coatings. The expression of osteoclastogenesis-related genes (RANKL and MCSF) in bone-marrow-derived mesenchymal cells (BMSCs) with the involvement of macrophages was decreased, whereas OPG expression was enhanced on SMS coatings compared to HA coatings, indicating that SMS coatings also downregulated the osteoclastogenesis. However, the osteogenic differentiation of BMSCs with the involvement of macrophages was comparable between SMS and HA coatings. Therefore, the prepared SMS coatings showed multidirectional effects, such as improving bonding strength, reducing inflammatory reaction, and downregulating osteoclastic activities, but maintaining a comparable osteogenesis, as compared with HA coatings. The combination of bioactive elements of Sr, Mg, and Si into bioceramic coatings can be a promising method to develop bioactive implants with multifunctional properties for orthopedic application.

It is accepted that the accelerated differentiation of tissue cells on bioactive materials is of great importance to regenerate the lost tissues. It was previously reported that lithium (Li) ions could enhance the in vitroproliferation and differentiation of retinoblastoma cells and endometrium epithelia by activating the Wnt canonical signalling pathway. It is interesting to incorporate Li ions into bioactive ceramics, such as β-tricalcium phosphate (Li-β-TCP), in order to stimulate both osteogenic and cementogenic differentiation of different stem cells for the regeneration of bone/periodontal tissues. Therefore, the aim of this study was to investigate the interactions of human periodontal ligament cells (hPDLCs) and human bone marrow stromal cells (hBMSCs) with Li-β-TCP bioceramic bulks and their ionic extracts, and further explore the osteogenic and cementogenic stimulation of Li-β-TCP bioceramics and the possible molecular mechanisms. The results showed that Li-β-TCP bioceramic disks supported the cell attachment and proliferation, and significantly enhanced bone/cementum-related gene expression, Wnt canonical signalling pathway activation for both hPDLCs and hBMSCs, compared to conventional β-TCP bioceramic disks without Li. The release of Li from Li-β-TCP powders could significantly promote the bone/cementum-related gene expression for both hPDLCs and hBMSCs compared to pure β-TCP extracts without Li release. Our results suggest that the combination of Li with β-TCP bioceramics may be a promising method to enhance bone/cementum regeneration as Li-β-TCP possesses excellent in vitroosteogenic and cementogenic stimulation properties by inducing bone/cementum-related gene expression in both hPDLCs and hBMSCs.

Mussels possess the ability to attach to virtually any type of inorganic and organic surfaces due to the existence of phenylalamine and lysine amino acids. Inspired by the property of mussels, polydopamine has been used for modifying bioinert materials, such as metals, semiconductors and plastics to improve their surface hydrophilicity. However, there are no reports about the effect of a polydopamine modification on apatite mineralization and the biological response of bioactive ceramics (not bioinert materials) for bone regeneration applications. Akermanite bioceramics (AKT, Ca2MgSi2O7) are a typical bioactive material with osteostimulation properties for bone tissue regeneration. The aim of this study is to systematically investigate the effect of a polydopamine modification on the physicochemical and biological properties of AKT bioceramics, including attachment, proliferation, ALP activity and bone-related gene expression of tissue cells. The results show that a self-assembled polydopamine layer on the surface of AKT bioceramics was formed by incubating AKT bioceramics in a dopamine/Tris–HCl solution. Polydopamine-modified AKT (PDB-AKT) bioceramics showed significantly improved surface roughness, hydrophilicity and apatite-mineralization ability compared to AKT bioceramics. In addition, the polydopamine modification distinctively enhanced the attachment, proliferation, alkaline phosphate activity and bone-related gene expression of MC3T3 cells on AKT bioceramics. The possible reason for the improved cytocompatibility may be related to the improved surface roughness and apatite mineralization as well as the ionic environment at an early stage of cell culture. Our results suggest that the polydopamine modification is a viable method to further improve the apatite mineralization and biological response of bioactive ceramics for better bone regeneration applications, indicating that the polydopamine modification is a universal method to enhance the bioactivity for both bioinert and bioactive materials.

Silicon (Si) is a trace element, which plays an important role in human bone growth. Si has been incorporated into biomaterials for bone regeneration in order to improve their osteogenic potential, both in vitroand in vivo. Little is known, however, as to how Si ions elicit their biological response on bone-forming cells. The aim of this study was to investigate the effect of Si ions on the proliferation, differentiation, bone-related gene expression and cell signalling pathways of bone marrow stromal cells (BMSCs) by comparing the BMSC responses to different concentrations of NaCl and Na2SiO3, while taking into account and excluding the effect of Na ions. Our study showed that Si ions at a concentration of 0.625 mM significantly enhanced the proliferation, mineralization nodule formation, bone-related gene expression (OCN, OPNand ALP) and bone matrix proteins (ALP and OPN) of BMSCs. Furthermore, Si ions at 0.625 mM could counteract the effect of the WNT inhibitor (W.I.) cardamonin on the osteogenic genes expression, (OPN, OCNand ALP), WNT and SHH signalling pathway-related genes in BMSCs. These results suggest that Si ions by themselves play an important role in regulating the proliferation and osteogenic differentiation of BMSCs, with the involvement of WNT and SHH signalling pathways. Our study provides evidence to explain possible molecular mechanisms whereby Si ions released from Si-containing biomaterials can acquire enhanced bioactivity at desired concentration.

The impact of bone diseases and trauma in the whole world has increased significantly in the past decades. Bioactive glasses are regarded as an important bone regeneration material owing to their generally excellent osteoconductivity and osteostimulativity. A new class of bioactive glass, referred to as mesoporous bioglass (MBG), was developed 7 years ago, which possess a highly ordered mesoporous channel structure and a highly specific surface area. The study of MBG for drug/growth factor delivery and bone tissue engineering has grown significantly in the past several years. In this article, we review the recent advances of MBG materials, including the preparation of different forms of MBG, composition–structure relationship, efficient drug/growth factor delivery and bone tissue engineering application. By summarizing our recent research, the interaction of MBG scaffolds with bone-forming cells, the effect of drug/growth factor delivery on proliferation and differentiation of tissue cells and the in vivoosteogenesis of MBG scaffolds are highlighted. The advantages and limitations of MBG for drug delivery and bone tissue engineering have been compared with microsize bioactive glasses and nanosize bioactive glasses. The future perspective of MBG is discussed for bone regeneration application by combining drug delivery with bone tissue engineering and investigating the in vivoosteogenesis mechanism in large animal models.