Shell-Sheddable Polymeric Micelles Alleviate Oxidative Stress and Inflammation for Enhanced Ischemic Stroke Therapy.

As a ROS scavenger, resveratrol exerts a neuroprotective effect by polarizing the M1 microglia to the anti-inflammatory M2 phenotype for ischemic stroke treatment. However, the obstruction of the blood-brain barrier (BBB) seriously impairs the efficacy of resveratrol. Herein, we develop a stepwise targeting nanoplatform for enhanced ischemic stroke therapy, which is fabricated by pH-responsive poly(ethylene glycol)-acetal-polycaprolactone-poly(ethylene glycol) (PEG-Acetal-PCL-PEG) and modified with cRGD and triphenylphosphine (TPP) on a long PEG chain and a short PEG chain, respectively. The as-designed micelle system features effective BBB penetration through cRGD-mediated transcytosis. Once entering the ischemic brain tissues and endocytosed by microglia, the long PEG shell can be detached from the micelles in the acidic lysosomes, subsequently exposing TPP to target mitochondria. Thus, the micelles can effectively alleviate oxidative stress and inflammation by enhanced delivery of resveratrol to microglia mitochondria, reversing the microglia phenotype through the scavenging of ROS. This work offers a promising strategy to treat ischemia-reperfusion injury.

Pressure-Gradient Counterwork of Dual-Fuel Driven Nanocarriers in Abnormal Interstitial Fluids for Enhancing Drug Delivery Efficiency.

The abnormal pressure in tumor tissue is a significant limitation on the drug delivery efficiency of tumor therapy. This work reports a gradient-driven nanomotor as drug nanocarrier with the pressure-counterworking function. The dual-fuel nanomotors are formed by co-electrospinning of the photosensitive polymers with calcium peroxide (CaO2 ) and catalase (CAT), followed by ultraviolet (UV) irradiation and bovine serum albumin (BSA) incubation. The UV-responsive cleavage nanomotors can effectively release O2 molecules at the fractures as a driving force to increase the delivery speed and escape the phagocytosis of macrophage system in normal tissues. Furthermore, CAT catalyzes H2 O2 produced by CaO2 and the tumor interstitial fluids to provide stronger power for the nanomotors. Additionally, according to the analysis of directional motions of the nanomotors, the functional relationship between the rotational diffusion coefficient (DR ) and the physiological viscosity is constructed. The dual-fuel nanocarriers enable up to 13.25% of the injected dose (ID)/per gram tissue and significantly improve the penetration in deep tumor. It is of vital importance to design and obtain the adaptive pressure-gradient counterworking nanomotors, which can effectively improve the drug delivery efficiency in vitro and in vivo.

Ice-Inspired Superlubricated Electrospun Nanofibrous Membrane for Preventing Tissue Adhesion.

Inspired by the superlubricated surface (SLS) of ice, which consists of an ultrathin and contiguous layer of surface-bound water, we built a SLS on the polycaprolactone (PCL)/poly(2-methacryloxyethylphosphorylcholine) (PMPC) composite nanofibrous membrane via electrospinning under controlled relative humidity (RH). The zwitterionic PMPC on the nanofiber provided a surface layer of bound water, thus generating a hydration lubrication surface. Prepared under 20% RH, electrospun PCL/PMPC nanofibers reached a minimum coefficient of friction (COF) of about 0.12 when the weight ratio of PMPC to PCL was 0.1. At a higher RH, a SLS with an ultralow COF of less than 0.05 was formed on the composite nanofibers. The high stability of the SLS hydration layer on the engineered nanofibrous membrane effectively inhibited fibroblast adhesion and markedly reduced tissue adhesion during tendon repair in vivo. This work demonstrates the great potential of this ice-inspired SLS approach in tissue adhesion-prevention applications.

A Biomimetic Polymer Magnetic Nanocarrier Polarizing Tumor-Associated Macrophages for Potentiating Immunotherapy.

The progress of antitumor immunotherapy is usually limited by tumor-associated macrophages (TAMs) that account for the highest proportion of immunosuppressive cells in the tumor microenvironment, and the TAMs can also be reversed by modulating the M2-like phenotype. Herein, a biomimetic polymer magnetic nanocarrier is developed with selectively targeting and polarizing TAMs for potentiating immunotherapy of breast cancer. This nanocarrier PLGA-ION-R837 @ M (PIR @ M) is achieved, first, by the fabrication of magnetic polymer nanoparticles (NPs) encapsulating Fe3 O4 NPs and Toll-like receptor 7 (TLR7) agonist imiquimod (R837) and, second, by the coating of the lipopolysaccharide (LPS)- treated macrophage membranes on the surface of the NPs for targeting TAMs. The intracellular uptake of the PIR @ M can greatly polarize TAMs from M2 to antitumor M1 phenotype with the synergy of Fe3 O4 NPs and R837. The relevant mechanism of the polarization is deeply studied through analyzing the mRNA expression of the signaling pathways. Different from previous reports, the polarization is ascribed to the fact that Fe3 O4 NPs mainly activate the IRF5 signaling pathway via iron ions instead of the reactive oxygen species-induced NF-κB signaling pathway. The anticancer effect can be effectively enhanced through potentiating immunotherapy by the polarization of the TAMs in the combination of Fe3 O4 NPs and R837.

Multistage Targeting Strategy Using Magnetic Composite Nanoparticles for Synergism of Photothermal Therapy and Chemotherapy.

Mitochondrial-targeting therapy is an emerging strategy for enhanced cancer treatment. In the present study, a multistage targeting strategy using doxorubicin-loaded magnetic composite nanoparticles is developed for enhanced efficacy of photothermal and chemical therapy. The nanoparticles with a core-shell-SS-shell architecture are composed of a core of Fe3 O4 colloidal nanocrystal clusters, an inner shell of polydopamine (PDA) functionalized with triphenylphosphonium (TPP), and an outer shell of methoxy poly(ethylene glycol) linked to the PDA by disulfide bonds. The magnetic core can increase the accumulation of nanoparticles at the tumor site for the first stage of tumor tissue targeting. After the nanoparticles enter the tumor cells, the second stage of mitochondrial targeting is realized as the mPEG shell is detached from the nanoparticles by redox responsiveness to expose the TPP. Using near-infrared light irradiation at the tumor site, a photothermal effect is generated from the PDA photosensitizer, leading to a dramatic decrease in mitochondrial membrane potential. Simultaneously, the loaded doxorubicin can rapidly enter the mitochondria and subsequently damage the mitochondrial DNA, resulting in cell apoptosis. Thus, the synergism of photothermal therapy and chemotherapy targeting the mitochondria significantly enhances the cancer treatment.

A Nanoplatform with Precise Control over Release of Cargo for Enhanced Cancer Therapy.

The development of a nanocarrier delivery system having both sufficient stability in blood circulation and a rapid drug release profile at target sites remains a major challenge in cancer therapy. Here, a multifunctional star-shaped micellar system with a precisely spatiotemporal control of releasing encapsulated agents is developed by mixing a photoinitiated crosslinking amphiphilic copolymer with a phenylboronic acid (PBA)-functionalized redox-sensitive amphiphilic copolymer for the first time. The combination of the functional polymers effectively resolves the contradiction that the micellar system cannot release the rapid drug release in cells when it possesses an extreme stability that is often required in blood circulation. In this system, the inner core polymers are photo-crosslinked, endowing a stable micelle matrix structure; the end groups of the hydrophilic segments are decorated with PBA ligands, providing an active targeting ability; disulfide bonds in the micellar matrix impart a redox-responsive trigger for the prompt intracellular release of drugs. As a result, with a relatively low DOX dosage (2 mg kg(-1) per injection) the in vivo antitumor effect on H22-bearing BALB/c mice shows that the micelles have a high therapeutic efficacy against solid tumors while minimal side effects against normal tissues.

A Dynamically Tunable, Bioinspired Micropatterned Surface Regulates Vascular Endothelial and Smooth Muscle Cells Growth at Vascularization.

Regulation of the growth of vascular endothelial cells (ECs) and smooth muscle cells (SMCs) with artificial vascular grafts at vascularization is well-known to regenerate functional blood vessels for treating cardiovascular disease; however, little research has been published on this subject. Here, a novel polymer vascular graft is presented, whose inner surface contains an assembled circular microgroove pattern decorated with a combination of concentric circular microgrooves and radial, straight microgrooves inspired by the orientation of SMCs and ECs in natural tissues. The surface micropatterns can produce dynamically tunable variations via the thermally switched shape memory. The results from the in vitro EC/SMC co-cultures reveal that the surface micropatterns have a great capacity to regulate the specific distribution of ECs/SMCs because the ECs grow along the radial, straight microgrooves and the SMCs grow along concentric circular microgrooves. The in vivo vascularization is further analyzed by implanting the vascular graft in the rabbit carotid artery. Both histological analysis and immunofluorescence staining demonstrate that it is capable of highly effectively capturing ECs and SMCs in the blood and subsequent regeneration of new blood vessels. Therefore, this study opens a new possibility for regenerating neovessels to replace and repair damaged vessels for cardiovascular diseases treatment.

Fabrication and Characterization of a Glucose-sensitive Antibacterial Chitosan-Polyethylene Oxide Hydrogel.

A novel glucose-sensitive chitosan-polyethylene oxide (CS/PEO =1:0.5~1:2.5) hydrogel with controlled release of metronidazole (MNZ) was obtained by chemical cross-linking and immobilization of glucose oxidase (GOx). The hydrogel was characterized by Fourier-transformed infrared spectroscopy (FTIR), compressive mechanical test, rheological analysis, cytotoxicity test, and antibacterial test against Porphyromonas gingivalis. The study found that the CS-PEO composite hydrogel possessed significantly better mechanical properties and biocompatibility than a single-component hydrogel. This might result from the physical cross-linking and formation of semi-interpenetrating network (semi-IPN). In addition, this novel hydrogel has self-regulate ability to release MNZ in response to the environmental glucose stimulus. Specifically, it released more drugs at higher glucose concentration, thus can lead to a greater ability to inhibit Porphyromonas gingivalis. This study has demonstrated the glucose-sensitive antibacterial hydrogel has a great potential as a new therapeutic material for treatment or prevention of periodontitis in diabetic patients.

Development of a bone targeted thermosensitive liposomal doxorubicin formulation based on a bisphosphonate modified non-ionic surfactant.

Bone is among the most common sites of metastasis in cancer patients, so it is an urgent need to develop drug delivery systems targeting tumor bone metastasis with the feature of controlled release. This study aimed to delivery of thermosensitive liposomal doxorubicin to bone for tumor metastasis treatment. First, Brij78 (polyoxyethylene stearyl ether) was conjugated with Pamidronate (Pa). By incorporating Pa-Brij78 to DPPC/Chol liposomes, we developed Pa surface functionalized liposomes. The Pa-Brij78/DPPC/Chol liposomes (PB-liposomes) exhibited a stronger binding affinity to hydroxyapatite (HA), a major component of bone, than Brij78/DPPC/Chol liposomes (B-liposomes). Doxorubicin (Dox) was then encapsulated in PB-liposomes and the results demonstrated complete release of Dox from PB-liposomes or the complex of HA/PB-liposomes within 10 min at 42 °C. Next, human lung cancer A549 cells were treated with the thermosensitive complex of HA/PB-liposomes/Dox to mimic tumor bone metastasis treatment through bone targeted delivery of therapeutic agents. Pre-incubation of HA/PB-liposomes/Dox with mild heat at 42 °C induced subsequent higher cytotoxicity to A549 cells than incubation of the same complex at 37 °C, suggesting more active drug release triggered by heat. In conclusion, we synthesized a novel surfactant Pa-Brij78 and it has the potential to be used for development of a bone targeted thermosensitive liposome formulation for treatment of tumor bone metastasis.

Delivery of growth factors using a smart porous nanocomposite scaffold to repair a mandibular bone defect.

Implantation of a porous scaffold with a large volume into the body in a convenient and safe manner is still a challenging task in the repair of bone defects. In this study, we present a porous smart nanocomposite scaffold with a combination of shape memory function and controlled delivery of growth factors. The shape memory function enables the scaffold with a large volume to be deformed into its temporal architecture with a small volume using hot-compression and can subsequently recover its original shape upon exposure to body temperature after it is implanted in the body. The scaffold consists of chemically cross-linked poly(ε-caprolactone) (c-PCL) and hydroxyapatite nanoparticles. The highly interconnected pores of the scaffold were obtained using the sugar leaching method. The shape memory porous scaffold loaded with bone morphogenetic protein-2 (BMP-2) was also fabricated by coating the calcium alginate layer and BMP-2 on the surface of the pore wall. Under both in vitro and in vivo environmental conditions, the porous scaffold displays good shape memory recovery from the compressed shape with deformed pores of 33 µm in diameter to recover its porous shape with original pores of 160 µm in diameter. In vitro cytotoxicity based on the MTT test revealed that the scaffold exhibited good cytocompatibility. The in vivo micro-CT and histomorphometry results demonstrated that the porous scaffold could promote new bone generation in the rabbit mandibular bone defect. Thus, our results indicated that this shape memory porous scaffold demonstrated great potential for application in bone regenerative medicine.

Co-delivery of dexamethasone and green tea polyphenols using electrospun ultrafine fibers for effective treatment of keloid.

PURPOSE: The electrospun polymer ultrafine fiber meshes wereused to co-deliver dexamethasone (DEX) and green tea polyphenols (GTP) in order to acquire a suitable balance between effective treament of keloid and safety to the skin. METHODS: This co-delivery system was prepared with a simple electrospinning technology. Keloid model was established on the back of athymic nude mice with the human keloid tissues and the formulated fiber meshes were applied onto keloids for an in vivo evaluation on their therapeutic effects. RESULTS: Unlike other therapeutic formulations, these fiber meshes as a new surgical dressing possess multiple useful functions, including the capabilities of maintaining a moist environment, resisting bacterial infection and controlling the drug release. Hydrophobic DEX molecules inside the fiber meshes can be released successfully from the channels formed by the early release of the hydrophilic GTP molecules and then transported across the skin. A distinctive result acquired from histological analysis shows that after 3-month treatment, the DEX/GTP-loaded fiber meshes significantly induce the degradation of collagen fibers in keloid on the back of nude mice compared to the traditional treatment. CONCLUSION: The dressing formulation based on nanofibers provides a promising platform for the treatment of keloid.

A Solvent-Templated Porous Liquid Crystal Elastomer with Tactile Sensation beyond Reversible Actuation toward Versatile Artificial Muscles.

Liquid crystal elastomers (LCEs), as a classical two-way shape-memory material, are good candidates for developing artificial muscles that mimic the contraction, expansion, or rotational behavior of natural muscles. However, biomimicry is currently focused more on the actuation functions of natural muscles dominated by muscle fibers, whereas the tactile sensing functions that are dominated by neuronal receptors and synapses have not been well captured. Very few studies have reported the sensing concept for LCEs, but the signals were still donated by macroscopic actuation, that is, variations in angle or length. Herein, we develop a conductive porous LCE (CPLCE) using a solvent (dimethyl sulfoxide (DMSO))-templated photo-cross-linking strategy, followed by carbon nanotube (CNT) incorporation. The CPLCE has excellent reversible contraction/elongation behavior in a manner similar to the actuation functions of skeletal muscles. Moreover, the CPLCE shows excellent pressure-sensing performance by providing real-time electrical signals and is capable of microtouch sensing, which is very similar to natural tactile sensing. Furthermore, macroscopic actuation and tactile sensation can be integrated into a single system. Proof-of-concept studies reveal that the CPLCE-based artificial muscle is sensitive to external touch while maintaining its excellent actuation performance. The CPLCE with tactile sensation beyond reversible actuation is expected to benefit the development of versatile artificial muscles and intelligent robots.

Degradable and Recyclable Hydrogels for Sustainable Bioelectronics.

Hydrogel bioelectronics has been widely used in wearable sensors, electronic skin, human-machine interfaces, and implantable tissue-electrode interfaces, providing great convenience for human health, safety, and education. The generation of electronic waste from bioelectronic devices jeopardizes human health and the natural environment. The development of degradable and recyclable hydrogels is recognized as a paradigm for realizing the next generation of environmentally friendly and sustainable bioelectronics. This review first summarizes the wide range of applications for bioelectronics, including wearable and implantable devices. Then, the employment of natural and synthetic polymers in hydrogel bioelectronics is discussed in terms of degradability and recyclability. Finally, this work provides constructive thoughts and perspectives on the current challenges toward hydrogel bioelectronics, providing valuable insights and guidance for the future evolution of sustainable hydrogel bioelectronics.

Micropatterned shape-memory polymer substrate containing hydrogen bonds creates a long-term dynamic microenvironment for regulating nerve-cell fate.

Peripheral nerve injuries (PNIs) caused by mechanical contusion are frequently encountered in clinical practice, using nerve guidance conduits (NGCs) is now a promising therapy. An NGC creates a microenvironment for cell growth and differentiation, thus understanding physical and biochemical cues that can affect nerve-cell fate is a prerequisite for rationally designing NGCs. However, most of the previous works were focused on some static cues, the dynamic nature of the nerve microenvironment has not yet been well captured. Herein, we develop a micropatterned shape-memory polymer as a programmable substrate for providing a dynamic cue for nerve-cell growth. The shape-memory properties enable temporal programming of the substrate, and a dynamic microenvironment is created during standard cell culturing at 37 °C. Unlike most of the biomedical shape-memory polymers that recover rapidly at 37 °C, the proposed substrate shows a slow recovery process lasting 3-4 days and creates a long-term dynamic microenvironment. Results demonstrate that the vertically programmed substrates provide the most suitable dynamic microenvironment for PC12 cells as both the differentiation and maturity are promoted. Overall, this work provides a strategy for creating a long-term dynamic microenvironment for regulating nerve-cell fate and will inspire the rational design of NGCs for the treatment of PNIs.

Antigen-Capturing Dendritic-Cell-Targeting Nanoparticles for Enhanced Tumor Immunotherapy Based on Photothermal-Therapy-Induced In Situ Vaccination.

In situ vaccines have revolutionized immunotherapy as they can stimulate tumor-specific immune responses, with the cancer being the antigen source. However, the heterogeneity of tumor antigens and insufficient dendritic cells (DCs) activation result in low cancer immunogenicity and hence poor vaccine response. Herein, a new in situ vaccine composed of acid-responsive liposome-coated polydopamine (PDA) nanoparticles modified with mannose and loaded with resiquimod (R848) is designed to promote the efficacy of immunotherapy. The in situ vaccine can actively target the tumor site based on the decomposition of the liposome, while the PDA nanoparticles promote photothermal therapy and capture the immunogenic cell-death-induced tumor-associated antigens based on the adsorption effect of dopamine-mimetic mussels. The PDA nanoparticles, which are modified with a mannose ligand, target the DCs and release R848 for activated antigen presentation. As a result, the in situ vaccine not only effectively activates the maturation of the DCs but also significantly enhances their effect on cytotoxic T lymphocyte cells. Furthermore, the vaccine effectively inhibits the distant recurrence and metastasis of tumors via long-term immune memory effects. Therefore, the in situ vaccine provides a potential strategy for improving the efficacy of cancer immunotherapy.

Multifunctional Liposomes Remodeling Tumor Immune Microenvironment for Tumor Chemoimmunotherapy.

In the treatment of solid tumors, the complex barriers composed of cancer-associated fibroblasts (CAFs) prevent drug delivery and T cells infiltration into tumor tissues. Although nanocarriers hold great prospects in drug delivery, fibrosis causes the biological barrier and immunosuppressive tumor microenvironment (ITM) that impairs the anti-tumor efficacy of nanocarriers. Here, a small dendritic macromolecule loaded with doxorubicin (PAMAM-ss-DOX) (DP) is synthesized and encapsulated into pH-responsive nanoliposome, together with adjuvant toll-like receptor 7/8 (TLR7/8) agonist resiquimod (R848) and losartan (LOS). The pH-responsive liposome facilitates the simultaneous and effective delivery of DP, R848, and LOS, which can decompose and release these drugs under the acidic tumor microenvironment. The small sized DP (≈25 nm) with the ability to penetrate into tumor tissue and immunogenic cell death (ICD) can reverse the ITM and elicit immune response, which is equivalent to the effect of an in situ vaccine. Moreover, LOS reduces the activity of CAFs effectively, which can contribute to the infiltration of T cells. Therefore, this nano-platform provides a new therapeutic strategy for enhanced chemo-immunotherapy.

Folate Decoration Supports the Targeting of Camptothecin Micelles against Activated Hepatic Stellate Cells and the Suppression of Fibrogenesis.

As the central cellular player in fibrogenesis, activated hepatic stellate cells (aHSCs) are the major target of antifibrotic nanomedicines. Based on our finding that activated HSCs increase the expression of folate receptor alpha (FRα), we tried to apply folic acid (FA) decoration to generate an active drug-targeting at aHSCs and suppress hepato-fibrogenesis. FA-conjugated poly(ethylene glycol)-poly(ε-caprolactone) copolymers (PEG-PCL) were synthesized and self-assembled into the spherical micelles that owned a uniform size distribution averaging at 60 nm, excellent hemo- and cyto-compatibility, and pH-sensitive stability. These FA-modified micelles were preferentially ingested by aHSCs as expected and accumulated more in acutely CCl4 injured mouse livers compared to nondecorated counterparts. Such an aHSC targetability facilitated the loaded medicinal camptothecin (CPT) to achieve a greater therapeutic efficacy and inhibition of MF phenotypic genes in aHSCs. Encouragingly, though free CPT and nontargeting CPT micelles produced negligible curative outcomes, FA-decorated CPT micelles yielded effectively remedial effects in chronically CCl4-induced fibrotic mice, as represented by a significant shrinkage of aHSC population, suppression of fibrogenesis, and recovery of liver structure and function, clearly indicating the success of the folate decoration-supported aHSC-targeted strategy for antifibrotic nanomedicines in fibrosis resolution.

Polyethylenimine functionalized magnetic nanoparticles as a potential non-viral vector for gene delivery.

Polyethylenimine (PEI) functionalized magnetic nanoparticles were synthesized as a potential non-viral vector for gene delivery. The nanoparticles could provide the magnetic-targeting, and the cationic polymer PEI could condense DNA and avoid in vitro barriers. The magnetic nanoparticles were characterized by Fourier transform infrared spectroscopy, X-ray powder diffraction, dynamic light scattering measurements, transmission electron microscopy, vibrating sample magnetometer and atomic force microscopy. Agarose gel electrophoresis was used to asses DNA binding and perform a DNase I protection assay. The Alamar blue assay was used to evaluate negative effects on the metabolic activity of cells incubated with PEI modified magnetic nanoparticles and their complexes with DNA both in the presence or absence of an external magnetic field. Flow cytometry and fluorescent microscopy were also performed to investigate the transfection efficiency of the DNA-loaded magnetic nanoparticles in A549 and B16-F10 tumor cells with (+M) or without (-M) the magnetic field. The in vitro transfection efficiency of magnetic nanoparticles was improved obviously in a permanent magnetic field. Therefore, the magnetic nanoparticles show considerable potential as nanocarriers for gene delivery.

A shape memory stent of poly(ε-caprolactone-co-DL-lactide) copolymer for potential treatment of esophageal stenosis.

Biodegradable polymer stent with shape memory effect is expected to be developed in the treatment of esophageal stenosis, most likely due to traditional stents having such shortages as considerable rigidity and nondegradation. A tubular stent with the inner and outer diameters of 28 and 30 mm was manufactured from biodegradable poly(ε-caprolactone-co-DL-lactide) (PCLA) copolymer consisting of ε-caprolactone and DL-lactide at a weight ratio of 10/90. A series of tests were accomplished to investigate its properties including shape memory effects (SMEs), compression property and influence of in vitro degradation of polymer matrix on its shape recovery and dilation force. Significantly, an implantation of the stent into a dog model was performed to evaluate its function for the treatment of esophageal stenosis. The deformed stent needs about 36 s to recover its initial shape in vitro in 37°C warm water. The primary animal experiment in vivo has revealed that the implanted deformed stent could be triggered by body temperature and expectedly returned to a nearly-round shape to support esophageal wall. Therefore, the biodegradable intelligent polymer stent may be great potential to displace the conventional metallic stents for the esophageal stenosis therapy.

A Hierarchical-Structured Mineralized Nanofiber Scaffold with Osteoimmunomodulatory and Osteoinductive Functions for Enhanced Alveolar Bone Regeneration.

Alveolar bone resorption is a major cause of teeth loss and jeopardizes the osseointegration of dental implants, greatly affecting patient's quality of life and health. It is still a great challenge to completely regenerate the alveolar bone defect through traditional guided bone regeneration (GBR) membranes due to their limited bioactivity and regeneration potential. Herein, a new hierarchical-structured mineralized nanofiber (HMF) scaffold, which is combined with both anisotropic and isotropic nanofibrous surface topography and the mineralized particles, is fabricated via a simple template-assisted electrospinning technology and in situ mineralization method. This HMF scaffold can not only directly induce osteogenic differentiation of bone mesenchymal stem cells (osteoinduction), but also stimulate macrophage toward pro-healing (M2) phenotype-polarization with an elevated secretion of the pro-healing cytokines, eventually enhancing the osteogenesis (osteoimmunomodulation). The results of in vivo rat alveolar bone defect repair experiments demonstrate that as compared with the combination of commercial Bio-Gide and Bio-Oss, the single HMF scaffold shows comparable or even superior bone repair effect, with better tissue-integration and more suitable degradation time and accompanied by a simplified operation.