A bioactive calcium silicate nanowire-containing hydrogel for organoid formation and functionalization.

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/ß-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.

Assembled/Disassembled Modular Scaffolds for Multicellular Tissue Engineering.

The behavior of tissue resident cells can be influenced by the spatial arrangement of cellular interactions. Therefore, it is of significance to precisely control the spatial organization of various cells within multicellular constructs. It remains challenging to construct a versatile multicellular scaffold with ordered spatial organization of multiple cell types. Herein, a modular multicellular tissue engineering scaffold with ordered spatial distribution of different cell types is constructed by assembling varying cell-laden modules. Interestingly, the modular scaffolds can be disassembled into individual modules to evaluate the specific contribution of each cell type in the system. Through assembling cell-laden modules, the macrophage-mesenchymal stem cell (MSC), endothelial cell-MSC, and chondrocyte-MSC co-culture models are successfully established. The in vitro results indicate that the intercellular cross-talk can promote the proliferation and differentiation of each cell type in the system. Moreover, MSCs in the modular scaffolds may regulate the behavior of chondrocytes through the nuclear factor of activated T-Cells (NFAT) signaling pathway. Furthermore, the modular scaffolds loaded with co-cultured chondrocyte-MSC exhibit enhanced regeneration ability of osteochondral tissue, compared with other groups. Overall, this work offers a promising strategy to construct a multicellular tissue engineering scaffold for the systematic investigation of intercellular cross-talk and complex tissue engineering.

In Situ Piezoelectric-Catalytic Anti-Inflammation Promotes the Rehabilitation of Acute Spinal Cord Injury in Synergy.

Relieving inflammation via scavenging toxic reactive oxygen species (ROS) during the acute phase of spinal cord injury (SCI) proves to be an effective strategy to mitigate secondary spinal cord injury and improve recovery of motor function. However, commonly used corticosteroid anti-inflammatory drugs show adverse side effects which may induce increased risk of wound infection. Fortunately, hydrogen (H2), featuring selective antioxidant performance, easy penetrability, and excellent biosafety, is being extensively investigated as a potential anti-inflammatory therapeutic gas for the treatment of SCI. In this work, by a facile in situ growth approach of gold nanoparticles (AuNPs) on the piezoelectric BaTiO3, a particulate nanocomposite with Schottky heterojunction (Au@BT) is synthesized, which can generate H2 continuously by catalyzing H+ reduction through piezoelectric catalysis. Further, theoretical calculations are employed to reveal the piezoelectric catalytic mechanism of Au@BT. Transcriptomics analysis and nontargeted large-scale metabolomic analysis reveal the deeper mechanism of the neuroprotective effect of H2 therapy. The as-prepared Au@BT nanoparticle is first explored as a flexible hydrogen gas generator for efficient SCI therapy. This study highlights a promising prospect of nanocatalytic medicine for disease treatments by catalyzing H2 generation; thus, offering a significant alternative to conventional approaches against refractory spinal cord injury.

Xonotlite Nanowire-Containing Bioactive Scaffolds for the Therapy of Defective Adipose Tissue in Breast Cancer.

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 Fe3O4 microspheres, Fe3O4-CS-GelMA scaffolds could effectively kill tumor cells in vitro and suppress breast cancer in vivo under 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.

Biological response of 3D-printedß-tricalcium phosphate bioceramic scaffolds with the hollow tube structure.

It is a large clinical challenge to repair critical-size bone defects, and vascularization in the early stage is of vital importance in bone regeneration. In recent years, 3D-printed bioceramic is a kind of common bioactive scaffold for repairing bone defects. However, conventional 3D-printed bioceramic scaffolds consist of stacked solid struts with low porosity, which limits the ability of angiogenesis and bone regeneration. The hollow tube structure can induce endothelial cells to build the vascular system. In this study,ß-tricalcium phosphate (ß-TCP) bioceramic scaffolds containing the hollow tube structure were prepared with digital light processing-based 3D printing strategy. The physicochemical properties and osteogenic activities of prepared scaffolds could be precisely controlled by adjusting the parameters of hollow tubes. Compared with solid bioceramic scaffolds, such scaffolds could significantly improve the proliferation and attachment activity of rabbit bone mesenchymal stem cellsin vitro, and facilitate early angiogenesis and subsequent osteogenesisin vivo. Therefore,ß-TCP bioceramic scaffolds with the hollow tube structure possess great potential application for the treatment of critical-size bone defects.

3D printing of gear-inspired biomaterials: Immunomodulation and bone regeneration.

It is of significance to construct the immunomodulatory and osteogenic microenvironment for three dimension (3D) regeneration of bone tissues. 3D scaffolds, with various chemical composition, macroporous structure and surface characteristics offer a beneficial microenvironment for bone tissue regeneration. However, there is a gap between the well-ordered surface microstructure of bioceramic scaffolds and immune microenvironment for bone regeneration. In this study, a gear-inspired 3D scaffold with well-ordered surface microstructure was successfully prepared through a modified extrusion-based 3D printing strategy for immunomodulation and bone regeneration. The prepared gear-inspired scaffolds could induce M2 phenotype polarization of macrophages and further promoted osteogenic differentiation of bone mesenchymal stem cells in vitro. The subsequent in vivo study demonstrated that the gear-inspired scaffolds were able to attenuate inflammation and further promote new bone formation. The study develops a facile strategy to construct well-ordered surface microstructure which plays a key role in 3D immunomodulatory and osteogenic microenvironment for bone tissue engineering and regenerative medicine. STATEMENT OF SIGNIFICANCE.

Bamboo-Based Biomaterials for Cell Transportation and Bone Integration.

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 H2 O 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.

Multiscale Hierarchical Architecture-Based Bioactive Scaffolds for Versatile Tissue Engineering.

Artificial construction from tendon to bone remains a formidable challenge in tissue engineering owing to their structural complexity. In this work, bioinspired calcium silicate nanowires and alginate composite hydrogels are utilized as building blocks to construct multiscale hierarchical bioactive scaffolds for versatile tissue engineering from tendon to bone. By integrating 3D printing technology and mechanical stretch post-treatment in a confined condition, the obtained composite hydrogels possess bioinspired reinforcement architectures from nano- to submicron- to microscale with significantly enhanced mechanical properties. The biochemical and topographical cues of the composite hydrogel scaffolds provide much more efficient microenvironment to the rabbit bone mesenchymal stem cells and rabbit tendon stem cells, leading to ordered alignment and improved differentiation. The composite hydrogels markedly promote in vivo tissue regeneration from bone to tendon, especially fibrocartilage transitional tissue. Therefore, such calcium silicate nanowires/alginate composite hydrogels with multiscale hierarchical structures have potential application for tissue regeneration from tendon to bone. This work provides an innovative strategy to construct multiscale hierarchical architecture-based scaffolds for tendon/bone engineering.

Spindle-Like Zinc Silicate Nanoparticles Accelerating Innervated and Vascularized Skin Burn Wound Healing.

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, Zn2 SiO4 (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.

Sprayable ß-FeSi2 composite hydrogel for portable skin tumor treatment and wound healing.

The development of a rapid-forming in-situ sprayable hydrogel with the functions of tumor treatment and wound healing is essential for eliminating residual tumor tissue and promoting wound healing caused by surgical resection. On account of its semiconductor properties, ß-FeSi2 (FS) was widely explored as a thermoelectric material. In this work, FS was first applied as a bioactive material for the application of tissue engineering. Excitedly, we found that FS could be used as a novel antitumor agent. It exhibited excellent photothermal performance, and the released Fe ions could generate •OH under the acidic conditions and excessive H2O2 in the tumor microenvironment. Moreover, the sprayable ß-FeSi2-incorporated sodium alginate (FS/SA) hydrogel was prepared as an instant gelation after spraying in situ, contributing to timely tumor-induced skin wound healing and efficiently suppressing tumors through photothermal and chemodynamic therapy (PTT and CDT). Furthermore, the released bioactive Fe and Si ions could promote the migration and differentiation of endothelial cells and the pro-angiogenesis of skin wounds. Accordingly, such sprayable hydrogel played an effective role in emergency wound treatment with the advantage of convenience and portability. Overall, with incorporation of FS into the sprayable FS/SA hydrogel, the composite hydrogel possessed dual functions of tumor therapy and skin wound healing.

Microbially Catalyzed Biomaterials for Bone Regeneration.

Bone is a complex mineralized tissue composed of various organic (proteins, cells) and inorganic (hydroxyapatite, calcium carbonate) substances with micro/nanoscale structures. To improve interfacial bioactivity of bone-implanted biomaterials, extensive efforts are being made to fabricate favorable biointerface via surface modification. Inspired by microbially catalyzed mineralization, a novel concept to biologically synthesize the micro/nanostructures on bioceramics, microbial-assisted catalysis, is presented. It involves three processes: bacterial adhesion on biomaterials, production of CO3 2- assisted by bacteria, and nucleation and growth of CaCO3 nanocrystals on the surface of bioceramics. The microbially catalyzed biominerals exhibit relatively uniform micro/nanostructures on the surface of both 2D and 3D α-CaSiO3 bioceramics. The topographic and chemical cues of the grown micro/nanostructures present excellent in vitro and in vivo bone-forming bioactivity. The underlying mechanism is closely related to the activation of multiple biological processes associated with bone regeneration. The study offers a microbially catalytic concept and strategy of fabricating micro/nanostructured biomaterials for tissue regeneration.

Development and Application of 3D Bioprinted Scaffolds Supporting Induced Pluripotent Stem Cells.

Three-dimensional (3D) bioprinting is a revolutionary technology that replicates 3D functional living tissue scaffolds in vitro by controlling the layer-by-layer deposition of biomaterials and enables highly precise positioning of cells. With the development of this technology, more advanced research on the mechanisms of tissue morphogenesis, clinical drug screening, and organ regeneration may be pursued. Because of their self-renewal characteristics and multidirectional differentiation potential, induced pluripotent stem cells (iPSCs) have outstanding advantages in stem cell research and applications. In this review, we discuss the advantages of different bioinks containing human iPSCs that are fabricated by using 3D bioprinting. In particular, we focus on the ability of these bioinks to support iPSCs and promote their proliferation and differentiation. In addition, we summarize the applications of 3D bioprinting with iPSC-containing bioinks and put forward new views on the current research status.

3D Printing of Black Bioceramic Scaffolds with Micro/Nanostructure for Bone Tumor-Induced Tissue Therapy.

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.

3D Printed Wesselsite Nanosheets Functionalized Scaffold Facilitates NIR-II Photothermal Therapy and Vascularized Bone Regeneration.

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 [SrCuSi4 O10 ] 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.

Manganese silicate nanospheres-incorporated hydrogels：starvation therapy and tissue regeneration.

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 O2 for tumor starvation. Meanwhile, hyperthermia triggered by near infrared (NIR) irradiation could not only accelerate the reaction rate of H2O2 decomposition 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.

Bifunctional, Copper-Doped, Mesoporous Silica Nanosphere-Modified, Bioceramic Scaffolds for Bone Tumor Therapy.

In the traditional surgical intervention procedure, residual tumor cells may potentially cause tumor recurrence. In addition, large bone defects caused by surgery are difficult to self-repair. Thus, it is necessary to design a bioactive scaffold that can not only kill residual tumor cells but also promote bone defect regeneration simultaneously. Here, we successfully developed Cu-containing mesoporous silica nanosphere-modified ß-tricalcium phosphate (Cu-MSN-TCP) scaffolds, with uniform and dense nanolayers with spherical morphology via 3D printing and spin coating. The scaffolds exhibited coating time- and laser power density-dependent photothermal performance, which favored the effective killing of tumor cells under near-infrared laser irradiation. Furthermore, the prepared scaffolds favored the proliferation and attachment of rabbit bone marrow-derived mesenchymal stem cells and stimulated the gene expression of osteogenic markers. Overall, Cu-MSN-TCP scaffolds can be considered for complete eradication of residual bone tumor cells and simultaneous healing of large bone defects, which may provide a novel and effective strategy for bone tumor therapy. In the future, such Cu-MSN-TCP scaffolds may function as carriers of anti-cancer drugs or immune checkpoint inhibitors in chemo-/photothermal or immune-/photothermal therapy of bone tumors, favoring for effective treatment.

A hydrogenated black TiO2 coating with excellent effects for photothermal therapy of bone tumor and bone regeneration.

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.

Mussel-Inspired Nanostructures Potentiate the Immunomodulatory Properties and Angiogenesis of Mesenchymal Stem Cells.

The therapeutic effects of mesenchymal stem cells (MSCs)-material constructs mainly come from the secretion of trophic factors from MSCs, especially the immunomodulatory and angiogenic cytokines. Recent findings indicate the significance of topographical cues from these materials in modulating paracrine functions of MSCs. Here, we developed functionalized three-dimensional-printed bioceramic (BC) scaffolds with a mussel-inspired surface coating in order to regulate the paracrine function of adipose-derived MSCs (Ad-MSCs). We found that Ad-MSCs cultured on polydopamine-modified BC scaffolds (DOPA-BC) significantly produced more immunomodulatory and pro-angiogenic factors when compared with those cultured on BC scaffolds or microplates. Functional assays, such as endothelial progenitor cells migration, tube formation, and macrophage polarization, were performed to confirm the enhanced paracrine functions of the secreted trophic factors from Ad-MSCs cultured on DOPA-BC scaffolds. Further investigation identified that both focal adhesion kinase- and extracellular signal-related kinase signaling were the required mechano-transduction pathways through which the mussel-inspired surface stimulated the paracrine effect of Ad-MSCs. In a diabetic skin-defect-healing model in rats, conditioned medium received from the Ad-MSCs cultured on DOPA-BC sped wound closure, enhanced vascularization, and promoted macrophage switching from a proinflammatory M1 to a pro-healing and anti-inflammatory M2 phenotype in the wound bed. These results demonstrate that a bio-inspired coating with polydopamine represents an effective method to enhance the paracrine function of MSCs. Our findings illustrate a novel strategy to accelerate tissue regeneration by guiding the paracrine-signaling network.

Grape Seed-Inspired Smart Hydrogel Scaffolds for Melanoma Therapy and Wound Healing.

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.