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Designing scaffolds that can regulate the innate immune response and promote vascularized bone regeneration holds promise for bone tissue engineering. Herein, electrospun scaffolds that combined physical and biological cues were fabricated by anchoring reparative M2 macrophage–derived exosomes onto topological pore structured nanofibrous scaffolds. The topological pore structure of the fiber and the immobilization of exosomes increased the nanoscale roughness and hydrophilicity of the fibrous scaffold. In vitro cell experiments showed that exosomes could be internalized by target cells to promote cell migration, tube formation, osteogenic differentiation, and anti-inflammatory macrophage polarization. The activation of fibrosis, angiogenesis, and macrophage was elucidated during the exosome-functionalized fibrous scaffold–mediated foreign body response (FBR) in subcutaneous implantation in mice. The exosome-functionalized nanofibrous scaffolds also enhanced vascularized bone formation in a critical-sized rat cranial bone defect model. Importantly, histological analysis revealed that the biofunctional scaffolds regulated the coupling effect of angiogenesis, osteoclastogenesis, and osteogenesis by stimulating type H vessel formation. This study elaborated on the complex processes within the cell microenvironment niche during fibrous scaffold–mediated FBR and vascularized bone regeneration to guide the design of implants or devices used in orthopedics and maxillofacial surgery. How to design scaffold materials that can regulate the local immune niche and truly achieve functional vascularized bone regeneration still remain an open question. Here, combining physical and biological cues, we proposed new insight to cell-free and growth factor-free therapy, anchoring reparative M2 macrophage–derived exosomes onto topological pore structured nanofibrous scaffolds. The exosomes functionalized-scaffold system mitigated foreign body response, including excessive fibrosis, tumor-like vascularization, and macrophage activation. Importantly, the biofunctional scaffolds regulated the coupling effect of angiogenesis, osteoclastogenesis, and osteogenesis by stimulating type H vessel formation. [Display omitted] [ABSTRACT FROM AUTHOR]

Building of multifunctional coatings in a more effective way is crucial for meeting the multilevel requirements of regenerative medicine. Herein, inspired by diatom and mussel, a specific but universal approach is proposed for building multifunctional coatings on slow‐degradable and fast‐degradable scaffolds or various substrates by using epigallocatechin gallate (EGCG) and polyethyleneimine (PEI) as bridges of silicon coupling. The results reveal that the polyphenol EGCG facilitates silica precipitation and coating topological morphology in synergy with PEI, and realizes antioxidant and immunomodulatory effects. The introduction of EGCG and the release of silicon ions present effective modulation of the immune microenvironment and remarkable promotion of angiogenesis and osteogenesis. The EGCG/silica coating strategy demonstrates a promising perspective for designing multifunctional coatings and optimizing tissue regeneration and reconstruction. [ABSTRACT FROM AUTHOR]

The interconnectivity of porous scaffold is vital for cell and tissue infiltration, and vascular networks formation, determining the successful bone regeneration in large bone defects. Here, inspired by the lotus‐root and Haversian system of natural bone, a nano‐hydroxyapatite/polyurethane (n‐HA/PU) lotus root‐like scaffold inlaid with micro holes on the wall of the adjacent channel was utilized to mediate cell biomineralization and vascularized bone tissue regeneration. Such a particular lotus‐type structure remarkably promoted cells to proliferate and infiltrate into the center of the entire scaffold, serving as a clue to account for regulating cell alignment and differentiation physically. In vitro studies suggested that apatite accumulated dramatically on the channel wall in the lotus‐type scaffold, probably promoting specific osteogenic differentiation of cells by the orientated channels, even in the absence of osteogenic factors. In vivo creation of critical bone defects (15‐mm segments) was done in the radius of rabbits and implanted with the scaffold of different geometry to assess the structural parameters on the efficacy of new bone regeneration. The more extensive positive staining of BMP‐2, more considerable amount of infiltrated capillary, more robust new bone formation, particularly the biomechanical strength of lotus‐type scaffold group could reach the level of the control group without surgery, indicating that the lotus‐type scaffold was more favorable for new bone tissue formation along tube‐like channels. These results highlighted the potential of this biomimetic scaffold for cell and tissue infiltration and thus repair large bony defects. [ABSTRACT FROM AUTHOR]

The fate of biomaterials is orchestrated by biocompatibility and bioregulation characteristics, reported to be closely related to topographical structures. For the purpose to investigate the topography of fibrous membranes on the guided bone regeneration performance, we successfully fabricated poly (lactate- co -glycolate)/fish collagen/nano-hydroxyapatite (PFCH) fibrous membranes with random, aligned and latticed topography by electrospinning. The physical, chemical and biological properties of the three topographical PFCH membranes were systematically investigated by in vitro and in vivo experiments. The subcutaneous implantation of C57BL6 mice showed an acceptable mild foreign body reaction of all three topological membranes. Interestingly, the latticed PFCH membrane exhibited superior abilities to recruit macrophage/monocyte and induce angiogenesis. We further investigated the osteogenesis of the three topographical PFCH membranes via the critical-size calvarial bone defect model of rats and mice and the results suggested that latticed PFCH membrane manifested promising performance to promote angiogenesis through upregulation of the HIF-1α signaling pathway; thereby enhancing bone regeneration. Our research illustrated that the topological structure of fibrous membranes, as one of the characteristics of biomaterials, could regulate its biological functions, and the fibrous structure of latticed topography could serve as a favorable surface design of biomaterials for bone regeneration. In material-mediated regeneration medicine, the interaction between the biomaterial and the host is key to successful tissue regeneration. The micro-and nano-structure becomes one of the most critical physical clues for designing biomaterials. In this study, we fabricated three topological electrospun membranes (Random, Aligned and Latticed) to understand how topological structural clues mediate bone tissue regeneration. Interestingly, we found that the Latticed topographical PFCH membrane promotes macrophage recruitment, angiogenesis, and osteogenesis in vivo , indicating the fibrous structure of latticed topography could serve as a favorable surface design of biomaterials for bone regeneration. [Display omitted] [ABSTRACT FROM AUTHOR]

Bone regeneration is an interdisciplinary complex lesson, including but not limited to materials science, biomechanics, immunology, and biology. Having witnessed impressive progress in the past decades in the development of bone substitutes; however, it must be said that the most suitable biomaterial for bone regeneration remains an area of intense debate. Since its discovery, poly (lactic-co-glycolic acid) (PLGA) has been widely used in bone tissue engineering due to its good biocompatibility and adjustable biodegradability. This review systematically covers the past and the most recent advances in developing PLGA-based bone regeneration materials. Taking the different application forms of PLGA-based materials as the starting point, we describe each form's specific application and its corresponding advantages and disadvantages with many examples. We focus on the progress of electrospun nanofibrous scaffolds, three-dimensional (3D) printed scaffolds, microspheres/nanoparticles, hydrogels, multiphasic scaffolds, and stents prepared by other traditional and emerging methods. Finally, we briefly discuss the current limitations and future directions of PLGA-based bone repair materials. As a key synthetic biopolymer in bone tissue engineering application, the progress of PLGA-based bone substitute is impressive. In this review, we summarized the past and the most recent advances in the development of PLGA-based bone regeneration materials. According to the typical application forms and corresponding crafts of PLGA-based substitutes, we described the development of electrospinning nanofibrous scaffolds, 3D printed scaffolds, microspheres/nanoparticles, hydrogels, multiphasic scaffolds and scaffolds fabricated by other manufacturing process. Finally, we briefly discussed the current limitations and proposed the newly strategy for the design and fabrication of PLGA-based bone materials or devices. [Display omitted] [ABSTRACT FROM AUTHOR]

Membranes play pivotal role in guided bone regeneration (GBR) technique for reconstruction alveolar bone. GBR membrane that is able to stimulate both osteogenic and angiogenic differentiation of cells may be more effective in clinic practice. Herein, we fabricated the Sr-doped calcium phosphate/polycaprolactone/chitosan (Sr-CaP/PCL/CS) nanohybrid fibrous membrane by incorporating 20 wt% bioactive Sr-CaP nanoparticles into PCL/CS matrix via one-step electrospinning method, in order to endow the membrane with stimulation of osteogenesis and angiogenesis. The physicochemical properties, mechanical properties, Sr2+ release behavior, and the membrane stimulate bone mesenchymal stem cell (BMSCs) differentiation were evaluated in comparison with PCL/CS and CaP/PCL/CS membranes. The SEM images revealed that the nanocomposite membrane mimicked the extracellular matrix structure. The release curve presented a 28-day long continuous release of Sr2+ and concentration which was certified in an optimal range for positive biological effects at each timepoint. The in vitro cell culture experiments certified that the Sr-CaP/PCL/CS membrane enjoyed excellent biocompatibility and remarkably promoted rat bone mesenchymal stem cell (BMSCs) adhesion and proliferation. In terms of osteogenic differentiation, BMSCs seeded on the Sr-CaP/PCL/CS membrane showed a higher ALP activity level and a better matrix mineralization. What's more, the synergism of the Sr2+ and CaP from the Sr-CaP/PCL/CS membrane enhanced BMSCs angiogenic differentiation, herein resulting in the largest VEGF secretion amount. Consequently, the Sr-CaP/PCL/CS nanohybrid electrospun membrane has promising applications in GBR. [ABSTRACT FROM AUTHOR]

Nano-hydroxyapatite (n-HA) reinforced poly(propylene carbonate) (PPC) composites were prepared for bone repair and reconstruction. The effects of reinforcement on the morphology, mechanical properties and biological performance of n-HA/PPC composites were investigated. The surface morphology and mechanical properties of the composites were characterized by scanning electron microscopy (SEM) and universal material testing machine. The analytical data showed that good incorporation and dispersion of n-HA crystals could be obtained in the PPC matrix at a 30:70 weight ratio. With the increase of n-HA content, the tensile strength increased and the fracture elongation rate decreased. In vitro cell culture revealed that the composite was favorable template for cell attachment and growth. In vivo implantation in femoral condyle defects of rabbits confirmed that the n-HA/PPC composite had good biocompatibility and gradual biodegradability, exhibiting good performance in guided bone regeneration. The results demonstrates that the incorporation of n-HA crystals into PPC matrix provides a practical way to produce biodegradable and cost-competitive composites mimicking the osteogenic niche for bone augmentation. [ABSTRACT FROM AUTHOR]

A nano-hydroxyapatite/polyamide 66 (nHA/PA66) composite with good bioactivity and osteoconductivity is employed to develop a novel porous membrane with an asymmetric structure. In order to investigate the biocompatibility and the effect on guided bone regeneration (GBR) of nHA/PA66 porous membrane, the proliferation, viability, morphology and alkaline phosphatase activity (ALP) of the osteoblast-like cell line (MG63) cultured on the membrane were studied in vitro. In vivo biocompatibility and osteogenesis of the fabricated membrane were assessed by comparing guiding rats calvarial bone defects regeneration with "gold standard" GBR material, expanded polytetrafluoroethylene (e-PTFE) membrane. In vitro experiments showed that the nHA/PA66 composite membrane had good cell affinity and cytocompatibility, in favor of cell proliferation. The in vivo study showed that the nHA/PA66 asymmetric porous membrane had a good GBR effect. All the results indicate that the asymmetric porous nHA/PA66 composite GBR membrane with good biocompatibility, high bioactivity and osteoconductivity exhibits good GBR effect and has a potential to be applied in GBR fields, especially in dental tissue regeneration. [ABSTRACT FROM AUTHOR]

In this study, nano-hydroxyapatite (n-HA) combined polycarbonate was synthesized by a novel method. The physical and chemical property of the composite was tested. The results indicated the n-HA a crystal has the similar grain size, phase composition and crystal structure as. TEM photos results show the n-HA crystals were uniformly distributed in the polymer matrix. Then, the chemical bond between inorganic n-HA and polycarbonate was investigated and discussed. Proliferation of MSCs/composite cultured for up to 11 days the adhesion were tested by MTT and SEM. The in vitro test confirmed that the n-HA/PC composite was biocompatible and no negative effect on MSCs has found. The composite is proved to be osteoconductive, and can stimulate the growth of new bone. These results indicated that the composite meet the basic requirement of bone substitute material, and be potentially applied for clinic. [ABSTRACT FROM AUTHOR]

Objectives: The bone tissue engineering primarily focuses on three‐dimensional co‐culture systems, which physical and biological properties resemble the cell matrix of actual tissues. The complex dialogue between bone‐forming and endothelial cells (ECs) in a tissue‐engineered construct will directly regulate angiogenesis and bone regeneration. The purpose of this study was to investigate whether co‐culture between osteogenic and angiogenic cells derived by bone mesenchymal stem cells (MSCs) could affect cell activities and new bone formation. Materials and methods: Mesenchymal stem cells were dually induced to differentiate into osteogenic cells (OMSCs) and ECs; both cell types were co‐cultured at different ratios to investigate their effects and underlying mechanisms through ELISA, RT‐qPCR and MTT assays. The selected cell mixture was transplanted onto a nano‐hydroxyapatite/polyurethane (n‐HA/PU) scaffold to form a cell‐scaffold construct that was implanted in the rat femoral condyles. Histology and micro‐CT were examined for further verification. Results: ELISA and gene expression studies revealed that co‐cultured OMSCs/ECs (0.5/1.5) significantly elevated the transcription levels of osteogenic genes such as ALP, Col‐I and OCN, as well as transcription factors Msx2, Runx2 and Osterix; it also upregulated angiogenic factors of vascular endothelial growth factor (VEGF) and CD31 when compared with cells cultured alone or in other ratios. The optimized OMSCs/ECs group had more abundant calcium phosphate crystal deposition, further facilitated their bone formation in vivo. Conclusions: The OMSCs/ECs‐scaffold constructs at an optimal cell ratio (0.5/1.5) achieved enhanced osteogenic and angiogenic factor expression and biomineralization, which resulted in more effective bone formation. [ABSTRACT FROM AUTHOR]

Polymer-based scaffolds with different degradability have been investigated to screen the matrix whose degradation rate is more closely matched with the bone regeneration rate. However, these comparisons are inclined to be compromised by the animal individual differences. In this study, we constructed an integrated scaffold model comprising four parts with different degradability and bioactivity to achieve an in situ comparison of bone regeneration ability of different scaffolds. Slow-degradable polycaprolactone (PCL), fast-degradable poly (lactic-co-glycolic acid) (PLGA), and silica-coated PCL and PLGA scaffolds were assembled into a round sheet to form a hydroxyapatite (HA)-free integrated scaffold. HA-doped PCL, PLGA, and silica-coated PCL and PLGA scaffolds were assembled to create an HA-incorporated integrated scaffold. The in vivo experimental results demonstrated that the local acid microenvironment caused by the rapid degradation of PLGA interfered with the osteogenic process promoted by PCL-based scaffolds in defect areas implanted with HA-free integrated scaffolds. Since the incorporation of HA alleviated the acidic microenvironment to some extent, each scaffold in HA-incorporated scaffolds exhibited its expected bone regeneration capacity. Consequently, it is feasible to construct an integrated structure for comparing the osteogenic effects of various scaffolds in situ, when there is no mutual interference between the materials. The strategy presented in this study inspired the structure design of biomaterials to enable in situ comparison of bone regeneration capacity of scaffolds. [Display omitted] • Bone repair effects of different scaffolds were compared in the same animal model. • An integrated structure composed of multiple parts with varying characteristics. • HA reduced the interference of PLGA acid-byproduct on osteogenesis of other parts. [ABSTRACT FROM AUTHOR]

Poly (lactic-co-glycolic acid) (PLGA) is a star biodegradable polymer widely studied and applied in the biomedical field. Improving the acidic microenvironment caused by its degradation products and regulating its degradation behavior are still urgent scientific and technological problems to be solved. In this study, to regulate the degradation behaviors of PLGA and improve its bioactivity, hydroxyapatite (HA) and magnesium oxide (MgO) were incorporated into PLGA substrate in different proportions and a series of 3D-printing PLGA/HA/MgO (PHM) composite porous scaffolds were prepared. Then the physicochemical properties, degradation behaviors, in vitro and in vivo biological performance of fabricated scaffolds were systematically studied. The in vitro experimental results showed that PHM composite scaffolds exhibited hydrophilic and mechanical properties similar to natural bone, the presence of MgO could effectively neutralize the acidic environment, and promote bone marrow stromal cells (BMSCs) adhesion, proliferation, and differentiation. The in vivo osteogenic experiments demonstrated that the PHM5 (25 wt% HA, 5 wt% MgO) scaffold could reduce the inflammatory response and promote new bone formation. This study provides a new idea for the regulation of the degradation behavior and the improvement of osteogenic properties of PLGA-based biomaterials. The prepared 3D-printed PHM5 scaffold shows great application potential in the bone repair field. [Display omitted] • PLGA/HA/MgO composite porous scaffolds were successfully prepared by 3D-printing. • MgO could effectively neutralize the acidic environment caused by PLGA degradation. • PLGA/HA/MgO scaffold could reduce inflammatory response and promote osteogenesis. • 3D-printed PLGA/HA/MgO scaffolds have great application potential in bone repair. [ABSTRACT FROM AUTHOR]

• Sr and SIM loaded hydroxyapatite microspheres were prepared by one-step approach. • Fabricated SrMHA-SIM can sustainable release strontium (Sr) and simvastatin (SIM) • SrMHA-SIM holds promise in promoting angiogenesis and osteogenesis. The development of multi-functional strontium (Sr) and simvastatin (SIM) loaded biomaterials to promote angiogenesis and osteogenesis is a promising therapeutic strategy. In order to overcome the complex synthesis process, low drug loading and burst release of drug-loaded biomaterials, in this study, we developed a microwave-assisted hydrothermal one-step approach to prepare Sr- and SIM-loaded hydroxyapatite microspheres for achieving long-term sustained-release of Sr and SIM. The developed one-step preparation method can maintain the chemical structure of simvastatin, and the drug loading rate of simvastatin can reach more than 30 wt%. The prepared double-loaded hydroxyapatite microspheres could sustainable release Sr and SIM for more than 35 days. The prepared hydroxyapatite microspheres containing Sr and SIM have a good application prospect in promoting bone formation. This simple and feasible one-step method can also provide reference for the preparation of other drug-loading microspheres. [ABSTRACT FROM AUTHOR]