Ion incorporation into bone grafting materials.

The use of biomaterials in regenerative medicine has expanded to treat various disorders caused by trauma or disease in orthopedics and dentistry. However, the treatment of large and complex bone defects presents a challenge, leading to a pressing need for optimized biomaterials for bone repair. Recent advances in chemical sciences have enabled the incorporation of therapeutic ions into bone grafts to enhance their performance. These ions, such as strontium (for bone regeneration/osteoporosis), copper (for angiogenesis), boron (for bone growth), iron (for chemotaxis), cobalt (for B12 synthesis), lithium (for osteogenesis/cementogenesis), silver (for antibacterial resistance), and magnesium (for bone and cartilage regeneration), among others (e.g., zinc, sodium, and silica), have been studied extensively. This review aims to provide a comprehensive overview of current knowledge and recent developments in ion incorporation into biomaterials for bone and periodontal tissue repair. It also discusses recently developed biomaterials from a basic design and clinical application perspective. Additionally, the review highlights the importance of precise ion introduction into biomaterials to address existing limitations and challenges in combination therapies. Future prospects and opportunities for the development and optimization of biomaterials for bone tissue engineering are emphasized.

Multilevel hierarchically ordered artificial biomineral.

Living organisms are known for creating complex organic-inorganic hybrid materials such as bone, teeth, and shells, which possess outstanding functions as compared to their simple mineral forms. This has inspired many attempts to mimic such structures, but has yielded few practical advances. In this study, a multilevel hierarchically ordered artificial biomineral (a composite of hydroxyapatite and gelatine) with favorable nanomechanical properties is reported. A typical optimized HAp/gelatin hybrid material in the perpendicular direction of the HAp c-axis has a modulus of 25.91 + 1.78 GPa and hardness of 0.90 + 0.10 GPa, which well matches that of human cortical bone (modulus 24.3 + 1.4 GPa, hardness 0.69 + 0.05 GPa). The bottom-up crystal constructions (from nano- to micro- to macroscale) of this material are achieved through a hard template approach by the phase transformation from DCP to HAp. The structural biomimetic material shows another way to mimic the complex hierarchical designs of sclerous tissues which have potential value for application in hard tissue engineering.

Immunomodulatory multicellular scaffolds for tendon-to-bone regeneration.

Limited motor activity due to the loss of natural structure impedes recovery in patients suffering from tendon-to-bone injury. Conventional biomaterials focus on strengthening the regenerative ability of tendons/bones to restore natural structure. However, owing to ignoring the immune environment and lack of multi-tissue regenerative function, satisfactory outcomes remain elusive. Here, combined manganese silicate (MS) nanoparticles with tendon/bone-related cells, the immunomodulatory multicellular scaffolds were fabricated for integrated regeneration of tendon-to-bone. Notably, by integrating biomimetic cellular distribution and MS nanoparticles, the multicellular scaffolds exhibited diverse bioactivities. Moreover, MS nanoparticles enhanced the specific differentiation of multicellular scaffolds via regulating macrophages, which was mainly attributed to the secretion of PGE2 in macrophages induced by Mn ions. Furthermore, three animal results indicated that the scaffolds achieved immunomodulation, integrated regeneration, and function recovery at tendon-to-bone interfaces. Thus, the multicellular scaffolds based on inorganic biomaterials offer an innovative concept for immunomodulation and integrated regeneration of soft/hard tissue interfaces.

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.

Lithium-Containing Biomaterials Stimulate Cartilage Repair through Bone Marrow Stromal Cells-Derived Exosomal miR-455-3p and Histone H3 Acetylation.

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.

3D-Printing of succulent plant-like scaffolds with beneficial cell microenvironments for bone regeneration.

Biomimetic materials with complicated structures inspired by natural plants play a critical role in tissue engineering. The succulent plants, with complicated morphologies, show tenacious vitality in extreme conditions due to the physiological functions endowed by their unique anatomical structures. Herein, inspired by the macroscopic structure of succulent plants, succulent plant-like bioceramic scaffolds were fabricated via digital laser processing 3D printing of MgSiO3. Compared with conventional scaffolds with interlaced columns, the structures could prevent cells from leaking from the scaffolds and enhance cell adhesion. The scaffold morphology could be well regulated by changing leaf sizes, shapes, and interlacing methods. The succulent plant-like scaffolds show excellent properties for cell loading as well as cell distribution, promoting cellular interplay, and further enhancing the osteogenic differentiation of bone marrow stem cells. The in vivo study further illustrated that the succulent plant-like scaffolds could accelerate bone regeneration by inducing the formation of new bone tissues. The study suggests that the obtained succulent plant-like scaffold featuring the plant macroscopic structure is a promising biomaterial for regulating cell distribution, enhancing cellular interactions, and further improving bone regeneration.

3D multicellular micropatterning biomaterials for hair regeneration and vascularization.

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 via bioprinting 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.

Cell-Laden Scaffolds for Vascular-Innervated Bone Regeneration.

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.

Polyhedron-Like Biomaterials for Innervated and Vascularized Bone Regeneration.

Neural-vascular networks are densely distributed through periosteum, cortical bone, and cancellous bone, which is of great significance for bone regeneration and remodeling. Although significant progress has been made in bone tissue engineering, ineffective bone regeneration, and delayed osteointegration still remains an issue due to the ignorance of intrabony nerves and blood vessels. Herein, inspired by space-filling polyhedra with open architectures, polyhedron-like scaffolds with spatial topologies are prepared via 3D-printing technology to mimic the meshwork structure of cancellous bone. Benefiting from its spatial topologies, polyhedron-like scaffolds greatly promoted the osteogenic differentiation of bone mesenchymal stem cells (BMSCs) via activating PI3K-Akt signals, and exhibiting satisfactory performance on angiogenesis and neurogenesis. Computational fluid dynamic (CFD) simulation elucidates that polyhedron-like scaffolds have a relatively lower area-weighted average static pressure, which is beneficial to osteogenesis. Furthermore, in vivo experiments further demonstrate that polyhedron-like scaffolds obviously promote bone formation and osteointegration, as well as inducing vascularization and ingrowth of nerves, leading to innervated and vascularized bone regeneration. Taken together, this work offers a promising approach for fabricating multifunctional scaffolds without additional exogenous seeding cells and growth factors, which holds great potential for functional tissue regeneration and further clinical translation.

Silicon-Based Biomaterials Modulate the Adaptive Immune Response of T Lymphocytes to Promote Osteogenesis/Angiogenesis via Epigenetic Regulation.

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.

3D printing of sponge spicules-inspired flexible bioceramic-based scaffolds.

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

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.

Cells-Micropatterning Biomaterials for Immune Activation and Bone Regeneration.

Natural tissues are composed of ordered architectural organizations of multiple tissue cells. The spatial distribution of cells is crucial for directing cellular behavior and maintaining tissue homeostasis and function. Herein, an artificial bone bioceramic scaffold with star-, Tai Chi-, or interlacing-shaped multicellular patterns is constructed. The "cross-talk" between mesenchymal stem cells (MSCs) and macrophages can be effectively manipulated by altering the spatial distribution of two kinds of cells in the scaffolds, thus achieving controllable modulation of the scaffold-mediated osteo-immune responses. Compared with other multicellular patterns, the Tai Chi pattern with a 2:1 ratio of MSCs to macrophages is more effective in activating anti-inflammatory M2 macrophages, improving MSCs osteogenic differentiation, and accelerating new bone formation in vivo. In brief, the Tai Chi pattern generates a more favorable osteo-immune environment for bone regeneration, exhibiting enhanced immunomodulation and osteogenesis, which may be associated with the activation of BMP-Smad, Oncostatin M (OSM), and Wnt/ß-catenin signaling pathways in MSCs mediated by macrophage-derived paracrine signaling mediators. The study suggests that the manipulation of cell distribution to improve tissue formation is a feasible approach that can offer new insights for the design of tissue-engineered bone substitutes with multicellular interactions.

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.

Three-Dimensional Printing of Scaffolds with Synergistic Effects of Micro-Nano Surfaces and Hollow Channels for Bone Regeneration.

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

3D-printed bioceramic scaffolds with Fe3S4microflowers for magnetothermal and chemodynamic therapy of bone tumor and regeneration of bone defects.

Elimination of residual osteosarcoma cells and repair of bone defects remain major challenges for osteosarcoma in clinic. To address this problem, it is required that multifunctional therapeutic platform possess high tumor-killing efficiency and simultaneous bone regeneration capabilities. In this work, an intelligent therapeutic platform was developed to achieve highly-efficient tumor therapy and simultaneous significantly improved bone defect repairing ability, which was realized byin situgrowing ferromagnetic Fe3S4layers with tuned microstructures on the surface of 3D-printed akermanite bioceramic scaffolds via hydrothermal method. The Fe3S4layers exploited magnetic thermal energy to enhance chemodynamic treatment, thus achieving a synergistic effect between magnetothermal and chemodynamic therapy on the elimination of residual tumor cells. Moreover, the micro-structured surface of the 3D-printed bioceramic scaffolds further enhanced the osteogenic activityin vitroand accelerated the bone regenerationin vivo. The scaffolds with multi-mode tumor-killing and bone repairing capabilities indicated that such a therapeutic platform is applicable for a stepwise treatment strategy of osteosarcoma and provides inspiration for the design of multifunctional biomaterials.

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.

Bone cements for therapy and regeneration for minimally invasive treatment of neoplastic bone defects.

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

3D Printing of Strontium Silicate Microcylinder-Containing Multicellular Biomaterial Inks for Vascularized Skin Regeneration.

The reconstruction of dermal blood vessels is essential for skin regeneration process. However, the lack of vascular structure, insufficient angiogenesis induction, and ineffective graft-host anastomosis of the existing skin substitutes are major bottle-necks for permanent skin replacement in tissue engineering. In this study, the uniform strontium silicate (SS) microcylinders are successfully synthesized and integrated into the biomaterial ink to serve as stable cell-induced factors for angiogenesis, and then a functional skin substitute based on a vascularization-induced biomimetic multicellular system is prepared via a "cell-writing" bioprinting technology. With an unprecedented combination of vascularized skin-mimicking structure and vascularization-induced function, the SS-containing multicellular system exhibits outstanding angiogenic activity both in vitro and in vivo. As a result, the bioprinted skin substitutes significantly accelerate the healing of both acute and chronic wounds by promoting the graft-host integration and vascularized skin regeneration in three animal models. Therefore, the study provides a referable strategy to fabricate biomimetic multicellular constructs with angiogenesis-induced function for regeneration of vascularized complex and hierarchical tissues.

Nanosized concave pit/convex dot microarray for immunomodulatory osteogenesis and angiogenesis.

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