Selenoprotein-Regulated Hydrogel for Ultrasound-Controlled Microenvironment Remodeling to Promote Bone Defect Repair

Abnormal levels of reactive oxygen species (ROS) and the hypoxic microenvironment within bone defects are important factors that impede bone repair processes. Herein, an innovative ultrasound-modulatable hydrogel platform with selenoprotein-mediated antioxidant effects to promote bone injury repair is presented. This hydrogel platform encapsulates oxygen-enriched selene-incorporated thin-shell silicon within methacrylate gelatin (O₂-PSSG). The resultant construct orchestrates the modulation of the bone-defect microenvironment, thereby expediting the course of bone regeneration. Ultrasound (US) is used to regulate the pore size of the hydrogel to release selenium-containing nanoparticles and promote the in situ synthesis of efficient intracellular selenoproteins and hydrogen peroxide consumption. As expected, O₂-PSSG rapidly releases selenocystine ([Sec]₂) under US control to scavenge reactive oxygen species and maintain the homeostasis of bone marrow mesenchymal stem cells (BMSCs). Over time, the action of the system by selenoprotein increases the activation of Wnt/β-catenin pathways and promotes the differentiation of BMSCs. Consequently, O₂-PSSG potentiates the antioxidant proficiency of BMSCs both in vitro and in vivo, alleviates hypoxic environments, promotes osteogenic differentiation, and expedites cranial bone repair in rat models. In summary, this study suggests that the designed and constructed US-responsive antioxidant hydrogel is a promising prospective strategy for addressing bone defects and fostering bone regeneration.     

Precipitation-Based Silk Fibroin Fast Gelling,Highly Adhesive,and Magnetic Nanocomposite Hydrogel for Repair of Irregular Bone Defects

Critical-sized bone defects, especially for irregular shapes, remain a significant challenge in orthopedics. Although various biomaterials are developed for bone regeneration, their application for repair of irregular bone defects is limited by the complicated preparation procedures involved, and their lack of shape-adaptive capacity, physiological adhesion, and potent osteogenic bioactivity. In the present study, a simple strategy of precipitation by introducing tannic acid (TA) with abundant phenolic hydroxyl groups and Fe₃O₄ nanoparticles, as metal-phenolic networks (MPN), is developed to easily prepare a fast gelling, shape-adaptive, and highly adhesive regenerated silk fibroin (RSF)/TA/Fe₃O₄ hydrogel system that can respond to a static magnetic field (SMF). The RSF/TA/Fe₃O₄ hydrogel exhibits sufficient adhesion in biological microenvironments and good osteogenic effect in vitro and in vivo, under an external SMF, and thus, can be applied to repair critical-sized bone defects. Moreover, bioinformatics analysis reveals that the synergistic mechanism of Fe₃O₄ NPs and SMF on osteogenic effects can be promotion of osteoblast differentiation via activation of the cyclic guanosine monophosphate (cGMP)/protein kinase G (PKG)/extracellular signal-regulated kinase (ERK) signaling pathway. This study provides a promising biomaterial with potential clinical application for the future treatment of (irregular) critical-sized bone defects.     

A Novel Hydrogel Surface Grafted With Dual Functional Peptides for Sustaining Long‐Term Self‐Renewal of Human Induced Pluripotent Stem Cells and Manipulating Their Osteoblastic Maturation

Realizing the clinical potential of human induced pluripotent stem cells (hiPSCs) in bone regenerative medicine requires the development of safe and chemically defined biomaterials for expansion of hiPSCs followed by directing their lineage commitment to osteoblasts. In this study, novel multipurpose peptide‐presenting hydrogel surfaces are prepared on common tissue culture plates via carboxymethyl chitosan grafting and subsequent immobilization of two functional peptides allowing for in vitro feeder‐free culture, long‐term self‐renewal, and osteogenic induction of hiPSCs. After vitronectin (VN) peptide modification, the engineered surfaces facilitate adhesion, proliferation, colony formation, and the maintenance of pluripotency of hiPSCs up to passage 10 under fully defined conditions without Matrigel or protein coating. Further, this synthetic niche exhibits an appealing regulatory effect on the osteogenic conversion of hiPSCs to osteoblastic phenotype without an embryoid body formation step by co‐decoration of different ratios of VN and bone‐forming peptide. Such a well‐defined, xeno‐free 2D engineered microenvironment not only helps to accelerate the clinical development of hiPSCs, but also provides a safe and robust platform for the generation of osteoblast‐like cells or bone‐like tissues at different maturation levels. Thus, the strategy may hold great potential for application in cell therapy and bone tissue engineering.     

Composite Colloidal Gels Made of Bisphosphonate‐Functionalized Gelatin and Bioactive Glass Particles for Regeneration of Osteoporotic Bone Defects

Injectable composite colloidal gels are developed for regeneration of osteoporotic bone defects through a bottom‐up assembly from bisphosphonate‐functionalized gelatin and bioactive glass particles. Upon bisphosphonate functionalization, gelatin nanoparticles show superior adhesion toward bioactive glass particles, resulting in elastic composite gels. By tuning their composition, these composite colloidal gels combine mechanical robustness with self‐healing ability. The composite colloidal gels support cell proliferation and differentiation in vitro without requiring any osteogenic supplement. In vivo evaluation of the composite colloidal gels reveals their capacity to support the regeneration of osteoporotic bone defects. Furthermore, the bisphosphonate modification of gelatin induces a therapeutic effect on the peri‐implantation region by enhancing the bone density of the osteoporotic bone tissue. Consequently, these composite colloidal gels offer new therapeutic opportunities for treatment of osteoporotic bone defects.     

Stem Cell-Niche Engineering via Multifunctional Hydrogel Potentiates Stem Cell Therapies for Inflammatory Bone Loss

Effective therapies capable of simultaneously inhibiting inflammation and promoting bone healing remain to be developed for inflammatory bone disease. Stem cell therapies hold great promise for a variety of diseases, but their translation is hampered by low cell survival, rapid clearance, and limited functional integration of transplanted stem cells in target tissues. Herein, a multifunctional hydrogel-based stem cell niche engineering strategy is reported for the treatment of inflammatory bone loss. By rationally integrating different functional modules, an injectable hydrogel-based stem niche is engineered, which possesses temperature-triggered gelling performance, inflammation/oxidative stress-resolving activity, stem-cell binding and survival-enhancing capacity, and osteogenesis-promoting capability. Using ectomesenchymal stem cells (EMSCs), effectiveness of this functionally advanced synthetic stem cell niche is demonstrated in rats with periodontitis, a representative inflammatory bone loss disease. Synergistic effects of the multifunctional hydrogel and EMSCs are also confirmed, with respect to normalizing the pathological microenvironment and improving alveolar bone regeneration in the periodontal tissue. Mechanistically, inflammation/oxidative stress-resolving and osteogenic differentiation promoting capacities of the synthetic stem cell niche are mainly achieved by an incorporated nanotherapy via the GDF15/Atf3/c-Fos axis of the MAPK signaling pathway. Besides periodontitis, the newly engineered hydrogel-stem cell therapies are promising for the treatment of other inflammatory bone defects.     

Remote Tuning of Built-In Magnetoelectric Microenvironment to Promote Bone Regeneration by Modulating Cellular Exposure to Arginylglycylaspartic Acid Peptide

Mimicking the endogenous physical microenvironment is a promising strategy for biomaterial-mediated tissue regeneration. However, precise control of physical cues such as electric/magnetic fields within extracellular environments to facilitate tissue regeneration remains a formidable challenge. Here, remote tuning of the magnetoelectric microenvironment is achieved by a built-in CoFe₂O₄/poly(vinylidene fluoridetrifluoroethylene) [P(VDF-TrFE)] magnetoelectric membrane for effective bone regeneration. The magnetoelectric microenvironment from the nanocomposite membranes promotes osteogenic differentiation of bone marrow mesenchymal stem cells (BM-MSCs) and enhances bone defect regeneration by increasing cellular exposure and integrin binding to arginylglycylaspartic acid peptide, as predicted by molecular dynamics simulations. Moreover, BM-MSCs are directed to the osteogenic lineage by osteoimmuomodulation which involves accelerating transition from an initial inflammatory immune response to a pro-healing regenerative immune response. This work offers a strategy to mimic the magnetoelectric microenvironment for achieving precise and effective tissue regenerative therapies, as well as provides fundamental insights into the biological effects driven by the built-in magnetoelectric membrane, which can be remotely tuned to precisely modulate osteogenesis in situ.     

Programming Delayed Dissolution Into Sacrificial Bioinks For Dynamic Temporal Control of Architecture within 3D-Bioprinted Constructs

Sacrificial printing allows introduction of architectural cues within engineered tissue constructs. This strategy adopts the use of a 3D-printed sacrificial ink that is embedded within a bulk hydrogel which is subsequently dissolved to leave open-channels. However, current conventional sacrificial inks do not recapitulate the dynamic nature of tissue development, such as the temporal presentation of architectural cues matching cellular requirements during different stages of maturation. To address this limitation, a new class of sacrificial inks is developed that exhibits tailorable and programmable delayed dissolution profiles (1–17 days), by exploiting the unique ability of the ruthenium complex and sodium persulfate initiating system to crosslink native tyrosine groups present in non-chemically modified gelatin. These novel sacrificial inks are also shown to be compatible with a range of biofabrication technologies, including extrusion-based printing, digital-light processing, and volumetric bioprinting. Further embedding these sacrificial templates within cell-laden bulk hydrogels displays precise control over the spatial and temporal introduction of architectural features into cell-laden hydrogel constructs. This approach demonstrates the unique capacity of delaying dissolution of sacrificial inks to modulate cell behavior, improving the deposition of mineralized matrix and capillary-like network formation in osteogenic and vasculogenic culture, respectively.     

Noncompressible Hemostasis and Bone Regeneration Induced by an Absorbable Bioadhesive Self-Healing Hydrogel

Bone bleeding and bone defects arising from trauma or bone tumor resection pose a great threat to patients and they are challenging problems to orthopedic surgeons. Traditional hemostatic materials are not suitable for bone fractures where compression cannot be applied, neither are they effective during surgeries where large amounts of body fluids prevent them from adhering to the large and irregular bone wound sites. This research introduces a catechol-conjugated chitosan (CHI-C) multi-functional hydrogel with adhesion, self-healing, cytocompatibility, hemocompatibility, and blood cell coagulation capacity. The hydrogel can be injected into internal and irregular bleeding sites and bone defective areas, and then rapidly self-heals (within 2 min) to an integrated hydrogel that fully fills the defective sites and strongly sticks to bleeding areas in the presence of body fluids during surgery. In vivo experiments using a rabbit ilium bone defect model demonstrate quick hemostasis after the hydrogel is applied and the blood loss is only ¼ compared to the untreated injuries. In addition, the bone regeneration is not interfered by the hydrogel and the bone defect is no longer visible with disappearance of the hydrogel after 4 weeks. This multi-functional hydrogel is potentially valuable for clinical applications towards tissue adhesion, hemostasis, and bone regeneration.     

Regulation of the Stem Cell–Host Immune System Interplay Using Hydrogel Coencapsulation System with an Anti‐Inflammatory Drug

The host immune system is known to influence mesenchymal stem cell (MSC)‐mediated bone tissue regeneration. However, the therapeutic capacity of hydrogel biomaterial to modulate the interplay between MSCs and T‐lymphocytes is unknown. Here it is shown that encapsulating hydrogel affects this interplay when used to encapsulate MSCs for implantation by hindering the penetration of pro‐inflammatory cells and/or cytokines, leading to improved viability of the encapsulated MSCs. This combats the effects of the host pro‐inflammatory T‐lymphocyte‐induced nuclear factor kappaB pathway, which can reduce MSC viability through the CASPASE‐3 and CASPASE‐8 associated proapoptotic cascade, resulting in the apoptosis of MSCs. To corroborate rescue of engrafted MSCs from the insult of the host immune system, the incorporation of the anti‐inflammatory drug indomethacin into the encapsulating alginate hydrogel further regulates the local microenvironment and prevents pro‐inflammatory cytokine‐induced apoptosis. These findings suggest that the encapsulating hydrogel can regulate the MSC‐host immune cell interplay and direct the fate of the implanted MSCs, leading to enhanced tissue regeneration.     

3D Molecularly Functionalized Cell‐Free Biomimetic Scaffolds for Osteochondral Regeneration

Clinically, cartilage damage is frequently accompanied with subchondral bone injuries caused by disease or trauma. However, the construction of biomimetic scaffolds to support both cartilage and subchondral bone regeneration remains a great challenge. Herein, a novel strategy is adopted to realize the simultaneous repair of osteochondral defects by employing a self‐assembling peptide hydrogel (SAPH) FEFEFKFK (F, phenylalanine; E, glutamic acid; K, lysine) to coat onto 3D‐printed polycaprolactone (PCL) scaffolds. Results show that the SAPH‐coated PCL scaffolds exhibit highly improved hydrophilicity and biomimetic extracellular matrix (ECM) structures compared to PCL scaffolds. In vitro experiments demonstrate that the SAPH‐coated PCL scaffolds promote the proliferation and osteogenic differentiation of rabbit bone mesenchymal stem cells (rBMSCs) and maintain the chondrocyte phenotypes. Furthermore, 3% SAPH‐coated PCL scaffolds significantly induce simultaneous regeneration of cartilage and subchondral bone after 8‐ and 12‐week implantation in vivo, respectively. Mechanistically, by virtue of the enhanced deposition of ECM in SAPH‐coated PCL scaffolds, SAPH with increased stiffness facilitates and remodels the microenvironment around osteochondral defects, which may favor simultaneous dual tissue regeneration. These findings indicate that the 3% SAPH provides efficient and reliable modification on PCL scaffolds and SAPH‐coated PCL scaffolds appear to be a promising biomaterial for osteochondral defect repair.     

Bioinspired Highly Anisotropic,Ultrastrong and Stiff,and Osteoconductive Mineralized Wood Hydrogel Composites for Bone Repair

Anisotropic hydrogels mimicking the biological tissues with directional functions play essential roles in damage-tolerance, cell guidance and mass transport. However, conventional synthetic hydrogels often have an isotropic network structure, insufficient mechanical properties and lack of osteoconductivity, which greatly limit their applications for bone repair. Herein, inspired by natural bone and wood, a biomimetic strategy is presented to fabricate highly anisotropic, ultrastrong and stiff, and osteoconductive hydrogel composites via impregnation of biocompatible hydrogels into the delignified wood followed by in situ mineralization of hydroxyapatite (HAp) nanocrystals. The well-aligned cellulose nanofibrils endow the composites with highly anisotropic structural and mechanical properties. The strong intermolecular bonds of the aligned cellulose fibrils and hydrogel/wood interaction, and the reinforcing nanofillers of HAp enable the composites remarkable tensile strength of 67.8 MPa and elastic modulus of 670 MPa, three orders of magnitude higher than those of conventional alginate hydrogels. More importantly, the biocompatible hydrogel together with aligned HAp nanocrystals could effectively promote osteogenic differentiation in vitro and induce bone formation in vivo. The bone ingrowth into the hydrogel composite scaffold also yields good osteointegration. This study provides a low-cost, eco-friendly, feasible, and scalable approach for fabricating anisotropic, strong, stiff, hydrophilic, and osteoconductive hydrogel composites for bone repair.     

Multifunctional Poly‐N‐Isopropylacrylamide/DNAzyme Microgels as Highly Efficient and Recyclable Catalysts for Biosensing

The development of highly efficient, recyclable, and multifunctional biocatalysts is of great importance for various applications, especially in biosensing. In this study, highly catalytic and recyclable DNAzyme functionalized poly‐N‐isopropylacrylamide (pNIPAM) microgels are prepared via one‐step precipitation polymerization. The pNIPAM/DNAzyme microgels exhibit highly catalytic activities in aqueous solution at room temperature, and become hydrophobic and separable from the reaction mixture at temperature higher than the lower critical solution temperature of pNIPAM, which facilitate the recyclable utilization of these catalysts. Different kinds of DNAzyme functionalized catalytic microgels can be facilely prepared via the one‐step synthesis procedure. Two typical catalytic DNA structures, the Mg²⁺‐dependent DNAzyme and the hemin‐G‐quadruplex horseradish peroxidase (HRP)‐mimicking DNAzyme, are chosen as model systems to validate the feasibility. These pNIPAM/DNAzyme microgel catalysts maintain 80% to 91% initial catalytic activity after eight times of catalysis recycling. Furthermore, the pNIPAM microgels by themselves provide additional interfaces to capturing an enzyme, glucose oxidase, which can cascade with the linked HRP mimicking DNAzymes, to form recyclable bi‐enzyme cascading system for the sensing of glucose.     

Self‐Supporting Graphene Hydrogel Film as an Experimental Platform to Evaluate the Potential of Graphene for Bone Regeneration

Graphene, a two dimensional carbonaceous material possessing a range of extraordinary properties, is considered promising for biomedical applications. Here, a simple form of graphene‐based bulk material–self‐supporting graphene hydrogel (SGH) film is used as a suitable platform to study the intrinsic properties of graphene both in vitro and in vivo. The free‐standing film show good cell adhesion, spreading, and proliferation. Films are implanted into subcutaneous sites of rats, and produce minimal fibrous capsule formation, and mild host tissue response in vivo. New blood vessel formation is also seen. The films swell and cracked in vivo, indicating the beginning of degradation. Of particular interest is that the film alone is found to be able to stimulate osteogenic differentiation of stem cells, without additional inducer, both in vitro and in vivo. Thus, this SGH film appears to be highly biocompatible and osteoinductive, demonstrating graphene's potential for bone regenerative medicine.     

Construction of Nanozyme‐Hydrogel for Enhanced Capture and Elimination of Bacteria

The widespread multidrug resistance resulting from the abuse of antibiotics motivates researchers to explore alternative methods to treat bacterial infections. Recently, the emergence of nanozymes has provided a potential approach to combat bacteria. Such nanozymes can mimic the functions of natural enzymes to induce the production of highly toxic reactive oxygen species (ROS) as an antibacterial. However, the lack of effective interaction between nanozymes and bacteria, and the intrinsic short lifetime and diffusion distance of ROS greatly compromise their bactericidal activity. Furthermore, the dead bacteria left in the infected area can give rise to unexpected tissue inflammation. Herein, for the first time, a nanozyme‐hydrogel is constructed to realize reinforced antibacterials. The nanozyme‐hydrogel with the traits of positive charge and macropore can capture and restrict bacteria in the range of ROS destruction. Significantly, by combining the near‐infrared photothermal property of nanozymes, the nanozyme‐hydrogel can achieve a synergistic bactericidal effect. More importantly, the nanozyme‐hydrogel can eliminate bacteria and reduce the risk of inflammation. In consequence, the current work manifests an original strategy to improve the antibacterial performance of nanozymes, concurrently promote wound healing.     

Wi-Fi对成骨细胞ROS的影响

通过对近距离（3 cm）暴露于2.45 GHz Wi-Fi射频辐射的MC3TC-E1细胞的比吸收率（specific absorption rate,SAR）和温度变化进行时域有限差分（finite-difference time-domain,FDTD）法仿真,检测细胞活性氧（reactive oxygen species,ROS）,探索体外培养的成骨细胞对2.45 GHz射频辐射能量的吸收和升温效应,及其非热效应对ROS的影响.研究结果表明:输出功率为500 mW 2.45 GHz Wi-Fi辐射90 min可使细胞平均温度升高0.5℃,升温最高点小于1℃;细胞培养皿总平均SAR值为0.835 6 W/kg,最大值为1.259 4 W/kg,最小值为0.553 7 W/kg;90 min 2.45 GHz Wi-Fi射频能量的非热效应可引起成骨细胞ROS的升高,ROS和SAR值正相关,Wi-Fi长时间辐射会影响骨的代谢.     

Regulation of Stem Cell Fate in a Three‐Dimensional Micropatterned Dual‐Crosslinked Hydrogel System

Micropatterning technology is a powerful tool for controlling the cellular microenvironment and investigating the effects of physical parameters on cell behaviors, such as migration, proliferation, apoptosis, and differentiation. Although there have been significant developments in regulating the spatial and temporal distribution of physical properties in various materials, little is known about the role of the size of micropatterned regions of hydrogels with different crosslinking densities on the response of encapsulated cells. In this study, a novel alginate hydrogel system that can be micropatterned three‐dimensionally is engineered to create regions that are crosslinked by a single mechanism or dual mechanisms. By manipulating micropattern size while keeping the overall ratio of single‐ to dual‐crosslinked hydrogel volume constant, the physical properties of the micropatterned alginate hydrogels are spatially tunable. When human adipose‐derived stem cells (hASCs) are photoencapsulated within micropatterned hydrogels, their proliferation rate is a function of micropattern size. Additionally, micropattern size dictates the extent of osteogenic and chondrogenic differentiation of photoencapsulated hASC. The size of 3D micropatterned physical properties in this new hydrogel system introduces a new design parameter for regulating various cellular behaviors, and this dual‐crosslinked hydrogel system provides a new platform for studying proliferation and differentiation of stem cells in a spatially controlled manner for tissue engineering and regenerative medicine applications.     

Spatiotemporalized Hydrogel Microspheres Promote Vascularized Osteogenesis via Ultrasound Oxygen Delivery

Disturbance of spatiotemporal oxygen balance is the main cause of delayed healing or nonhealing of large bone defects. The accurate administration of oxygen to regulate disruptions in the spatiotemporal oxygen equilibrium during 9 h of hypoxia is imperative for bone tissue regeneration. Herein, oxygen-loaded nanobubbles prepared by double emulsification are successfully embedded in GelMA/HepMA microsphere macromolecular meshwork by microfluidic techniques, and a spatiotemporalized hydrogel microsphere is constructed by noncovalently binding bone morphogenetic protein 2 (BMP-2). The spatiotemporalized hydrogel microspheres precisely “remote control” oxygen release by ultrasound in vitro 9 h after bone injury to regulate spatiotemporal oxygen homeostasis disorder, maintain a high level of vascular endothelial growth factor (VEGF) expression, and accelerate bone repair. The spatiotemporalized hydrogel microspheres possess good oxygen-carrying capacity and ultrasonic responsiveness, and the oxygen concentration increases to 1.63, 1.95, 2.11, and 2.29 times under the ultrasound action at different intensities of 1, 2, 3, and 4 W, respectively, providing the conditions for the precise regulation of spatiotemporal oxygen balance disorder by ultrasound. In the in vitro hypoxia model and in vivo rat femoral defect model, the spatiotemporal hydrogel microspheres show good vascularization and osteogenesis capabilities, which provide a new strategy for the clinical treatment of large bone defects.     

Direct 3D Printing of High Strength Biohybrid Gradient Hydrogel Scaffolds for Efficient Repair of Osteochondral Defect

The emerging 3D printing technique allows for tailoring hydrogel‐based soft structure tissue scaffolds for individualized therapy of osteochondral defects. However, the weak mechanical strength and uncontrollable swelling intrinsic to conventional hydrogels restrain their use as bioinks. Here, a high‐strength thermoresponsive supramolecular copolymer hydrogel is synthesized by one‐step copolymerization of dual hydrogen bonding monomers, N‐acryloyl glycinamide, and N‐[tris(hydroxymethyl)methyl] acrylamide. The obtained copolymer hydrogels demonstrate excellent mechanical properties—robust tensile strength (up to 0.41 MPa), large stretchability (up to 860%), and high compressive strength (up to 8.4 MPa). The rapid thermoreversible gel ? sol transition behavior makes this copolymer hydrogel suitable for direct 3D printing. Successful preparation of 3D‐printed biohybrid gradient hydrogel scaffolds is demonstrated with controllable 3D architecture, owing to shear thinning property which allows continuous extrusion through a needle and also immediate gelation of fluid upon deposition on the cooled substrate. Furthermore, this biohybrid gradient hydrogel scaffold printed with transforming growth factor beta 1 and β‐tricalciumphosphate on distinct layers facilitates the attachment, spreading, and chondrogenic and osteogenic differentiation of human bone marrow stem cells (hBMSCs) in vitro. The in vivo experiments reveal that the 3D‐printed biohybrid gradient hydrogel scaffolds significantly accelerate simultaneous regeneration of cartilage and subchondral bone in a rat model.     

A 3D Printable and Bioactive Hydrogel Scaffold to Treat Traumatic Brain Injury

Traumatic brain injury accompanied by intracranial hypertension remains one of the most fatal injuries worldwide. Usually, patients must undergo two surgeries, craniectomy and cranioplasty, to reduce the intracranial pressure and then repair the skull. Traditional biomaterials, such as autologous bones and titanium meshes, which have poor stretchability and very high Young's modulus values up to hundreds of GPa, tend to constrain intracranial tissue and cannot be implanted directly after craniectomy. Thus far, finding elastic and degradable biomaterials to be immediately implanted after a craniectomy has remained a great challenge, which should not only repair cranial defects but also avoid secondary surgery and reduce the risk of complications, has remained a great challenge. Herein, a 3D printable bioactive hydrogel scaffold with high elasticity that can protect brain tissue, adapt to intracranial pressure changes, allow for the transport of nutrients and the proliferation and osteogenic differentiation of bone mesenchymal stem cells is presented. As indicated by in vivo experiments, the hydrogel scaffold helps to treat traumatic brain injury within 8 weeks and degrades safely. With these advantages, this material shows the potential to open up new horizons for cranioplasty and to help patients survive traumatic brain injury.