Channeled β‐TCP Scaffolds Promoted Vascularization and Bone Augmentation in Mandible of Beagle Dogs

A major hindrance to successful alveolar bone augmentation and ridge preservation using synthetic scaffolds is insufficient vascularization in the implanted bone grafts. The slow ingrowth of host vasculature from the bone bed of alveolar bone to the top of the implanted bone grafts leads to limited bone formation in the upper layers of the implanted grafts, which hinders the subsequent implantation of titanium dental implants. In this study, macroporous beta‐tricalcium phosphate (β‐TCP) scaffolds with multiple vertical hollow channels are fabricated that play a similar role as blood vessels for nutrient diffusion and cell migration. The results show that the hollow channels accelerate the degradation rate of the β‐TCP scaffolds and the in vitro release of a bone forming peptide‐1, which significantly promote proliferation and osteogenesis of human bone mesenchymal stem cells on the channeled scaffolds, compared to nonchanneled scaffolds in vitro. More volume of newly formed bone tissues with more blood vessels are augmented in the channeled scaffolds when implanted in mandibular bone defects of beagle dogs. Channeled scaffolds significantly promote new bone formation and augment the height of the mandible. These findings indicate channeled scaffolds facilitate vascularization and bone formation and have great potential for vascularized bone augmentation.     

3D Superelastic Scaffolds Constructed from Flexible Inorganic Nanofibers with Self‐Fitting Capability and Tailorable Gradient for Bone Regeneration

Repair of bone defects with irregular shapes or at soft tissue insertion sites faces a huge challenge. Scaffolds capable of adapting to bone cavities, generating stiffness gradients, and inducing osteogenesis are necessary. Herein, a superelastic 3D ceramic fibrous scaffold is developed by assembly of intrinsically rigid, structurally flexible electrospun SiO₂ nanofibers with chitosan as bonding sites (SiO₂ NF‐CS) via a lyophilization technique. SiO₂ NF‐CS scaffolds exhibit excellent elasticity (full recovery from 80% compression), fast recovery rate (>500 mm min^?1), and good fatigue resistance (>10 000 cycles of compression) in an aqueous medium. SiO₂ NF‐CS scaffolds induce human mesenchymal stem cell (hMSC) elongation and differentiation into osteoblasts. In vivo self‐fitting capability is demonstrated by implanting compressed SiO₂ NF‐CS scaffolds into different shaped mandibular defects in rabbits, with a spontaneous recovery and full filling of defects. Rat calvarial defect repair validates enhanced bone formation and vascularization by cell (hMSC) histomorphology analysis. Further, subchondral bone scaffolds with gradations in SiO₂ nanofibers are developed, leading to a stiffness gradient and spatially chondrogenic and osteogenic differentiation of hMSCs. This work presents a type of 3D ceramic fibrous scaffold, which can closely match bone defects with irregular shapes or at different implant sites, and is promising for clinical translation.     

Silk Biomaterials with Vascularization Capacity

Functional vascularization is critical for the clinical regeneration of complex tissues such as kidney, liver, or bone. The immobilization or delivery of growth factors has been explored to improve vascularization capacity of tissue‐engineered constructs; however, the use of growth factors has inherent problems such as the loss of signaling capability and the risk of complications including immunological responses and cancer. Here, a new method of preparing water‐insoluble silk protein scaffolds with vascularization capacity using an all‐aqueous process is reported. Acid is added temporally to tune the self‐assembly of silk in the lyophilization process, resulting in water‐insoluble scaffold formation directly. These biomaterials are mainly noncrystalline, offering improved cell proliferation than previously reported silk materials. These systems also have an appropriate softer mechanical property that could provide physical cues to promote cell differentiation into endothelial cells, and enhance neovascularization and tissue ingrowth in vivo without the addition of growth factors. Therefore, silk‐based degradable scaffolds represent an exciting biomaterial option, with vascularization capacity for soft tissue engineering and regenerative medicine.     

Polymer Fiber Scaffolds for Bone and Cartilage Tissue Engineering

Successful regeneration of weight‐bearing bone defects and critical‐sized cartilage defects remains a major challenge in clinical orthopedics. In the past decades, biodegradable polymer materials with biomimetic chemical and physical properties have been rapidly developed as ideal candidates for bone and cartilage tissue engineering scaffolds. Due to their unique advantages over other materials of high specific‐surface areas, suitable mechanical strength, and tailorable characteristics, scaffolds made of polymer fibers have been increasingly used for the repair of bone and cartilage defects. This Review summarizes the preparation and compositions of polymer fibers, as well as their characteristics. More importantly, the applications of polymer fiber scaffolds with well‐designed structures or unique properties in bone, cartilage, and osteochondral tissue engineering have been comprehensively highlighted. On the whole, such a comprehensive summary affords constructive suggestions for the development of polymer fiber scaffolds in bone and cartilage tissue engineering.     

Arrayed Hollow Channels in Silk‐Based Scaffolds Provide Functional Outcomes for Engineering Critically Sized Tissue Constructs

In the field of regenerative medicine there is a need for scaffolds that support large, critically‐sized tissue formation. Major limitations in reaching this goal are the delivery of oxygen and nutrients throughout the bulk of the engineered tissue as well as host tissue integration and vascularization upon implantation. To address these limitations, the development of a porous scaffold platform made from biodegradable silk protein that contains an array of vascular‐like structures that extend through the bulk of the scaffold was previously reported. Here, the hollow channels play a pivotal role in enhancing cell infiltration, delivering oxygen and nutrients to the scaffold bulk, and promoting in vivo host tissue integration and vascularization. The unique features of this protein biomaterial system, including the vascular structures and tunable material properties, render this scaffold a robust and versatile tool for implementation in a variety of tissue engineering, regenerative medicine, and disease modeling applications.     

Near-Infrared Light Triggered Silk Fibroin Scaffold for Photothermal Therapy and Tissue Repair of Bone Tumors

Silk fibroin (SF) has attracted great interest in bone tissue engineering due to its extraordinary characteristics in terms of mechanical properties, biocompatibility, and biodegradability. SF scaffolds are assembled by biocompatible polydopamine nanoparticles at mesoscopic scale, which endows the scaffolds with a near-infrared (NIR) light response for the treatment of bone tumors. The functionalized SF scaffold not only enhances the significant structure and performance of native SF scaffold for bone treatment and reconstruction, such as primary and mesoscopic structure, multi-level pores, and biodegradation, as well as biocompatibility but also have excellent photothermal effect leading a significant cytotoxicity to MG63 cancer cells after NIR laser irradiation. Moreover, the penetration of NIR light in tissue is improved using an optical fiber, which demonstrates the obtained scaffolds’ great potential in the application of photothermal therapy.     

A Bi‐Lineage Conducive Scaffold for Osteochondral Defect Regeneration

Because cartilage and bone tissues have different lineage‐specific biological properties, it is challenging to fabricate a single type of scaffold that can biologically fulfill the requirements for regeneration of these two lineages simultaneously within osteochondral defects. To overcome this challenge, a lithium‐containing mesoporous bioglass (Li‐MBG) scaffold is developed. The efficacy and mechanism of Li‐MBG for regeneration of osteochondral defects are systematically investigated. Histological and micro‐CT results show that Li‐MBG scaffolds significantly enhance the regeneration of subchondral bone and hyaline cartilage‐like tissues as compared to pure MBG scaffolds, upon implantation in rabbit osteochondral defects for 8 and 16 weeks. Further investigation demonstrates that the released Li+ ions from the Li‐MBG scaffolds may play a key role in stimulating the regeneration of osteochondral defects. The corresponding mechanistic pathways involve Li+ ions enhancing the proliferation and osteogenic differentiation of bone mesenchymal stem cells (BMSCs) through activation of the Wnt signalling pathway, as well as Li+ ions protecting chondrocytes and cartilage tissues from the inflammatory osteoarthritis (OA) environment through activation of autophagy. These findings suggest that the incorporation of Li+ ions into bioactive MBG scaffolds is a viable strategy for fabricating bi‐lineage conducive scaffolds that enhance regeneration of osteochondral defects.     

Electrospun Photocrosslinkable Hydrogel Fibrous Scaffolds for Rapid In Vivo Vascularized Skin Flap Regeneration

Distal necrosis of random skin flap is always clinical problematic in plastic surgery. The development of 3D functional vascular networks is fundamental for the survival of a local random skin flap. Herein, an effective technique on constructing 3D fibrous scaffolds for accelerated vascularization is demonstrated using a photocrosslinkable natural hydrogel based on gelatin methacryloyl (GelMA) by electrospinning. It is found that the ultraviolet (UV) photocrosslinkable gelatin electrospun hydrogel fibrous membranes exhibit soft adjustable mechanical properties and controllable degradation properties. Furthermore, it is observed that the optimized hydrogel scaffolds can support endothelial cells and dermal fibroblasts adhesion, proliferation, and migration into the scaffolds, which facilitates vascularization. Importantly, a rapid formation of tubes is observed after 3 d seeding of endothelial cells. After GelMA fibrous scaffold implantation below the skin flap in a rat model, it is found that the flap survival rate is higher than the control group, and there is more microvascular formation, which is potentially beneficial for the flap tissue vascularization. These data suggest that GelMA hydrogels can be used for biomedical applications that require the formation of microvascular networks, including the development of complex engineered tissues.     

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.     

Black‐Phosphorus‐Incorporated Hydrogel as a Conductive and Biodegradable Platform for Enhancement of the Neural Differentiation of Mesenchymal Stem Cells

Conductive hydrogel scaffolds have important applications for electroactive tissue repairs. However, the development of conductive hydrogel scaffolds tends to incorporate nonbiodegradable conductive nanomaterials that will remain in the human body as foreign matters. Herein, a biodegradable conductive hybrid hydrogel is demonstrated based on the integration of black phosphorus (BP) nanosheets into the hydrogel matrix. To address the challenge of applying BP nanosheets in tissue engineering due to its intrinsic instability, a polydopamine (PDA) modification method is developed to improve the stability. Moreover, PDA modification also enhances interfacial bonding between pristine BP nanosheets and the hydrogel matrix. The incorporation of polydopamine‐modified black phosphorous (BP@PDA) nanosheets into the gelatin methacryloyl (GelMA) hydrogels significantly enhances the electrical conductivity of the hydrogels and improves the cell migration of mesenchymal stem cells (MSCs) within the 3D scaffolds. On the basis of the gene expression and protein level assessments, the BP@PDA‐incorporated GelMA scaffold can significantly promote the differentiation of MSCs into neural‐like cells under the synergistic electrical stimulation. This strategy of integrating biodegradable conductive BP nanomaterials within a biocompatible hydrogel provides a new insight into the design of biomaterials for broad applications in tissue engineering of electroactive tissues, such as neural, cardiac, and skeletal muscle tissues.     

Toward Strong and Tough Glass and Ceramic Scaffolds for Bone Repair

The need for implants to repair large bone defects is driving the development of porous synthetic scaffolds with the requisite mechanical strength and toughness in vivo. Recent developments in the use of design principles and novel fabrication technologies are paving the way to create synthetic scaffolds with promising potential for reconstituting bone in load‐bearing sites. Here, the state of the art in the design and fabrication of bioactive glass and ceramic scaffolds that have improved mechanical properties for structural bone repair is reviewed. Scaffolds with anisotropic and periodic structures can be prepared with compressive strengths comparable to human cortical bone (100?150 MPa), while scaffolds with an isotropic structure typically have strengths in the range of trabecular bone (2?12 MPa). However, the mechanical response of bioactive glass and ceramic scaffolds in multiple loading modes such as flexure and torsion—as well as their mechanical reliability, fracture toughness, and fatigue resistance—has received little attention. Inspired by the designs of natural materials such as cortical bone and nacre, glass‐ceramic and inorganic/polymer composite scaffolds created with extrinsic toughening mechanisms are showing potential for both high strength and mechanical reliability. Future research should include improved designs that provide strong scaffolds with microstructures conducive to bone ingrowth, and evaluation of these scaffolds in large animal models for eventual translation into clinical applications.     

Biomimetic Ultralight,Highly Porous,Shape‐Adjustable,and Biocompatible 3D Graphene Minerals via Incorporation of Self‐Assembled Peptide Nanosheets

Hybrid nanomaterials with tailored functions, consisting of self‐assembled peptides, are intensively applied in nanotechnology, tissue engineering, and biomedical applications due to their unique structures and properties. Herein, a peptide‐mediated biomimetic strategy is adopted to create the multifunctional 3D graphene foam (GF)‐based hybrid minerals. First, 2D peptide nanosheets (PNSs), obtained by self‐assembling a motif‐specific peptide molecule (LLVFGAKMLPHHGA), are expected to exhibit biofunctionality, such as the biomimetic mineralization of hydroxyapatite (HA) minerals. Subsequently, the noncovalent conjugation of PNSs onto GF support is utilized to form 3D GF‐PNSs hybrid scaffolds, which are suitable for the growth of HA minerals. The fabricated biomimetic 3D GF‐PNSs‐HA minerals exhibit adjustable shape, superlow weight (0.017 g cm^?3), high porosity (5.17 m² g^?1), and excellent biocompatibility, proving potential applications in both bone tissue engineering and biomedical engineering. To the best of the authors' knowledge, it is the first time to combine 2D PNSs and GF to fabricate 3D organic–inorganic hybrid scaffold. Further development of these hybrid GF‐PNSs scaffolds can potentially lead to materials used as matrices for drug delivery or bone tissue engineering as proven via successful 3D scaffold formation exhibiting interconnected pore‐size structures suitable for vascularization and medium transport.     

3D Printing Hydrogel Scaffolds with Nanohydroxyapatite Gradient to Effectively Repair Osteochondral Defects in Rats

Osteochondral (OC) defects pose an enormous challenge with no entirely satisfactory repair strategy to date. Herein, a 3D printed gradient hydrogel scaffold with a similar structure to that of OC tissue is designed, involving a pure hydrogel-based top cartilage layer, an intermediate layer for calcified cartilage with 40% (w w⁻¹) nanohydroxyapatite (nHA) and 60% (w w⁻¹) hydrogel, and a 70/30% (w w⁻¹) nHA/hydrogel-based bottom subchondral bone layer. This study is conducted to evaluate the efficacy of the scaffold with nHA gradients in terms of its ability to promote OC defect repair. The fabricated composites are evaluated for physicochemical, mechanical, and biological properties, and then implanted into the OC defects in 56 rats. Overall, bone marrow stromal cells (BMSCs)-loaded gradient scaffolds exhibit superior repair results as compared to other scaffolds based on gross examination, micro-computed tomography (micro-CT), as well as histologic and immunohistochemical analyses, confirming the ability of this novel OC graft to facilitate simultaneous regeneration of cartilage-subchondral bone.     

Solid Free‐Form Fabrication of Tissue‐Engineering Scaffolds with a Poly(lactic‐co‐glycolic acid) Grafted Hyaluronic Acid Conjugate Encapsulating an Intact Bone Morphogenetic Protein–2/Poly(ethylene glycol) Complex

Despite wide applications of bone morphogenetic protein–2 (BMP‐2), there are few methods to incorporate BPM‐2 within polymeric scaffolds while maintaining biological activity. Solid free‐form fabrication (SFF) of tissue‐engineering scaffold is successfully carried out with poly(lactic‐co‐glycolic acid) grafted hyaluronic acid (HA‐PLGA) encapsulating intact BMP‐2/poly(ethylene glycol) (PEG) complex. HA‐PLGA conjugate is synthesized in dimethyl sulfoxide (DMSO) by the conjugation reaction of adipic acid dihydrazide modified HA (HA‐ADH) and PLGA activated with N,N′‐dicyclohexylcarbodiimide (DCC) and N‐hydroxysuccinimide (NHS). BMP‐2 is complexed with PEG, which is encapsulated within the PLGA domain of the HA‐PLGA conjugate by SFF to prepare tissue‐engineering scaffolds. In vitro release tests confirm the sustained release of intact BMP‐2 from the scaffolds for up to a month. After confirmation of the enhanced osteoblast cell growth, and high gene‐expression levels of alkaline phosphatase (ALP), osteocalcin (OC), and osterix (OSX) in the cells, the HA‐PLGA/PEG/BMP‐2 scaffolds are implanted into calvarial bone defects of Sprague Dawley (SD) rats. Microcomputed tomography (μCT) and histological analyses with Masson's trichrome, and hematoxylin and eosin (H&E) staining reveal effective bone regeneration on the scaffolds of HA‐PLGA/PEG/BMP‐2 blends.     

A Bifunctional Biomaterial with Photothermal Effect for Tumor Therapy and Bone Regeneration

Malignant bone tumor is one of the major bone diseases. The treatment of such a bone disease typically requires the removal of bone tumor and regeneration of tumor‐initiated bone defects simultaneously. To address this issue, it is required that implanted biomaterials should combine the bifunctions of both therapy and regeneration. In this work, a bifunctional graphene oxide (GO)‐modified β‐tricalcium phosphate (GO‐TCP) composite scaffold combining a high photothermal effect with significantly improved bone‐forming ability is prepared by 3D‐printing and surface‐modification strategies. The prepared GO‐TCP scaffolds exhibit excellent photothermal effects under the irradiation of 808 nm near infrared laser (NIR) even at an ultralow power density of 0.36 W cm^?2, while no photothermal effects are observed for pure β‐TCP scaffolds. The photothermal temperature of GO‐TCP scaffolds can be effectively modulated in the range of 40–90 °C by controlling the used GO concentrations, surface‐modification times, and power densities of NIR. The distinct photothermal effect of GO‐TCP scaffolds induces more than 90% of cell death for osteosarcoma cells (MG‐63) in vitro, and further effectively inhibits tumor growth in mice. Meanwhile, the prepared GO‐TCP scaffolds possess the improved capability to stimulate the osteogenic differentiation of rabbit bone mesenchymal stem cells (rBMSCs) by upregulating bone‐related gene expression, and significantly promote new bone formation in the bone defects of rabbits as compared to pure β‐TCP scaffolds. These results successfully demonstrate that the prepared GO‐TCP scaffolds have bifunctional properties of photothermal therapy and bone regeneration, which is believed to pave the way to design and fabricate novel implanting biomaterials in combination of therapy and regeneration functions.     

4D Printing of Multi-Responsive Membrane for Accelerated In Vivo Bone Healing Via Remote Regulation of Stem Cell Fate

Dynamic regulation of substrate micro-structures is an effective strategy to control stem cell fate in tissue engineering. Translating this into in vivo tissue repair in a clinical setting remains challenging, which requires precise temporal control of multi-scale structural features. Using 4D printing technique, a multi-responsive bilayer morphing membrane consisting of a shape memory polymer (SMP) layer and a hydrogel layer, is fabricated. The SMP layer is featured with responsive surface micro-structures, which can switch the phase between proliferation and differentiation precisely, thus promoting the bone formation. The hydrogel layer endows the membrane with the ability to digitally regulate its 3D geometry, matching the specific macroscopic bone shape in clinical scenario. The authors’ in vivo experiments show that the 4D shape-shifting membrane exhibits over 30% improvement in new bone formation in comparison to a reference membrane with static micro-structure. More importantly, the 4D membrane can conformally wrap a bone defect model in a non-invasive way and this strategy can be extended to repairs involving complex tissue defects.     

Biomimetic Elastomeric Bioactive Siloxane‐Based Hybrid Nanofibrous Scaffolds with miRNA Activation: A Joint Physico‐Chemical‐Biological Strategy for Promoting Bone Regeneration

Rapid and efficient disease‐induced or critical‐size bone regeneration remains a challenge in tissue engineering due to the lack of highly bioactive biomaterial scaffolds. Physical structures such as nanostructures, chemical components such as silicon elements, and biological factors such as genes have shown positive effects on bone regeneration. Herein, a bioactive photoluminescent elastomeric silicate‐based nanofibrous scaffold with sustained miRNA release is reported for promoting bone regeneration based on a joint physico‐chemical‐biological strategy. Bioactive nanofibrous scaffolds are fabricated by cospinning poly (ε‐caprolactone) (PCL), elastomeric poly (citrates‐siloxane) (PCS), and bioactive osteogenic miRNA nanocomplexes (denoted PPM nanofibrous scaffolds). The PPM scaffolds possess uniform nanostructures, significantly enhanced tensile stress (≈15 MPa) and modulus (≈32 MPa), improved hydrophilicity (30–60°), controlled biodegradation, and strong blue fluorescence. Bioactive miRNA complexes are efficiently loaded into the nanofibrous matrix and exhibit long‐term release for up to 70 h. The PPM scaffolds significantly promote the adhesion, proliferation, and osteoblast differentiation of bone marrow stem cells in vitro and enhanced rat cranial defect restoration (12 weeks) in vivo. This work reports an attractive joint physico‐chemical‐biological strategy for the design of novel cell/protein‐free bioactive scaffolds for synergistic tissue regeneration.     

Apatite‐Binding Nanoparticulate Agonist of Hedgehog Signaling for Bone Repair

The hedgehog signaling pathway plays a critical role in bone development and regeneration. Applications of hedgehog morphogens or small molecular agonists are of interest in bone repair but constrained by low stability, high dose requirement, and nonspecific targeting in vivo. Herein, a nanoparticulate agonist as a new type of hedgehog signaling activator is developed for efficacious bone healing. The shell of nanoparticulate agonist consists of palmitic acid and oxysterol, which could modify hedgehog function and bind with the smoothened receptor to positively modulate hedgehog signaling. Meanwhile, the core is assembled with the sonic hedgehog gene/polyethyleneimine complex, which could synergistically enhance hedgehog signaling with oxysterol constituents. Moreover, alendronate is introduced into the nanoparticulate agonist to bind with hydroxyapatite for potential bone tissue targeting. Lastly, the nanoparticulate agonist surface is decorated with the guanidine group to overcome cell membrane barriers. The created multifunctional nanoparticulate agonist is successfully integrated onto apatite‐coated 3D scaffolds and demonstrates greatly improved osteogenesis in vitro and calvarial bone healing. This work suggests a novel biomaterial design to specifically promote hedgehog signaling for the treatment of bone defects.     

窄带多通道滤光片的设计与制备

介绍了三种获得窄带多通道滤光片的方法。第一种方法是具有缺陷的多异质结结构，该结构能够展宽光子晶体的禁带同时实现多通道效应。第二种方法是多通道导模共振布儒斯特滤光片，此类滤光片可以采用单层膜结构来实现多通道效应，也可以采用具有相等折射率的双层膜结构来实现多通道效应。第三种方法是组合刻蚀法制备窄带滤光片列阵。该方法不仅可以制作单腔窄带滤光片列阵，还可以制作双腔窄带滤光片列阵。窄带多通道滤光片在光学领域中具有一定的应用前景。