Electrospinning is a versatile and viable technique for generating ultrathin fibers. Remarkable progress has been made with regard to the development of electrospinning methods and engineering of electrospun nanofibers to suit or enable various applications. We aim to provide a comprehensive overview of electrospinning, including the principle, methods, materials, and applications. We begin with a brief introduction to the early history of electrospinning, followed by discussion of its principle and typical apparatus. We then discuss its renaissance over the past two decades as a powerful technology for the production of nanofibers with diversified compositions, structures, and properties. Afterward, we discuss the applications of electrospun nanofibers, including their use as "smart" mats, filtration membranes, catalytic supports, energy harvesting/conversion/storage components, and photonic and electronic devices, as well as biomedical scaffolds. We highlight the most relevant and recent advances related to the applications of electrospun nanofibers by focusing on the most representative examples. We also offer perspectives on the challenges, opportunities, and new directions for future development. At the end, we discuss approaches to the scale-up production of electrospun nanofibers and briefly discuss various types of commercial products based on electrospun nanofibers that have found widespread use in our everyday life.

Electrospinning and Electrospun Nanofibers: Methods, Materials, and Applications

The use of 3D printing for rapid tooling and manufacturing has promised to produce components with complex geometries according to computer designs. Due to the intrinsically limited mechanical properties and functionalities of printed pure polymer parts, there is a critical need to develop printable polymer composites with high performance. 3D printing offers many advantages in the fabrication of composites, including high precision, cost effective and customized geometry. This article gives an overview on 3D printing techniques of polymer composite materials and the properties and performance of 3D printed composite parts as well as their potential applications in the fields of biomedical, electronics and aerospace engineering. Common 3D printing techniques such as fused deposition modeling, selective laser sintering, inkjet 3D printing, stereolithography, and 3D plotting are introduced. The formation methodology and the performance of particle-, fiber- and nanomaterial-reinforced polymer composites are emphasized. Finally, important limitations are identified to motivate the future research of 3D printing.

3D printing of polymer matrix composites: A review and prospective

3D Printing promises to produce complex biomedical devices according to computer design using patient-specific anatomical data. Since its initial use as pre-surgical visualization models and tooling molds, 3D Printing has slowly evolved to create one-of-a-kind devices, implants, scaffolds for tissue engineering, diagnostic platforms, and drug delivery systems. Fueled by the recent explosion in public interest and access to affordable printers, there is renewed interest to combine stem cells with custom 3D scaffolds for personalized regenerative medicine. Before 3D Printing can be used routinely for the regeneration of complex tissues (e.g. bone, cartilage, muscles, vessels, nerves in the craniomaxillofacial complex), and complex organs with intricate 3D microarchitecture (e.g. liver, lymphoid organs), several technological limitations must be addressed. In this review, the major materials and technology advances within the last five years for each of the common 3D Printing technologies (Three Dimensional Printing, Fused Deposition Modeling, Selective Laser Sintering, Stereolithography, and 3D Plotting/Direct-Write/Bioprinting) are described. Examples are highlighted to illustrate progress of each technology in tissue engineering, and key limitations are identified to motivate future research and advance this fascinating field of advanced manufacturing.

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Recent advances in 3D printing of biomaterials

Poly(lactic-co-glycolic) acid (PLGA) has attracted considerable interest as a base material for biomedical applications due to its: (i) biocompatibility; (ii) tailored biodegradation rate (depending on the molecular weight and copolymer ratio); (iii) approval for clinical use in humans by the U.S. Food and Drug Administration (FDA); (iv) potential to modify surface properties to provide better interaction with biological materials; and (v) suitability for export to countries and cultures where implantation of animal-derived products is unpopular. This paper critically reviews the scientific challenge of manufacturing PLGA-based materials with suitable properties and shapes for specific biomedical applications, with special emphasis on bone tissue engineering. The analysis of the state of the art in the field reveals the presence of current innovative techniques for scaffolds and material manufacturing that are currently opening the way to prepare biomimetic PLGA substrates able to modulate cell interaction for improved substitution, restoration, or enhancement of bone tissue function.

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An Overview of Poly(lactic-co-glycolic) Acid (PLGA)-Based Biomaterials for Bone Tissue Engineering

This review analyzes the literature of bone grafts and introduces tissue engineering as a strategy in this field of orthopedic surgery. We evaluated articles concerning bone grafts; analyzed characteristics, advantages, and limitations of the grafts; and provided explanations about bone-tissue engineering technologies. Many bone grafting materials are available to enhance bone healing and regeneration, from bone autografts to graft substitutes; they can be used alone or in combination. Autografts are the gold standard for this purpose, since they provide osteogenic cells, osteoinductive growth factors, and an osteoconductive scaffold, all essential for new bone growth. Autografts carry the limitations of morbidity at the harvesting site and limited availability. Allografts and xenografts carry the risk of disease transmission and rejection. Tissue engineering is a new and developing option that had been introduced to reduce limitations of bone grafts and improve the healing processes of the bone fractures and defects. The combined use of scaffolds, healing promoting factors, together with gene therapy, and, more recently, three-dimensional printing of tissue-engineered constructs may open new insights in the near future.

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Bone regenerative medicine: classic options, novel strategies, and future directions

Objectives Exosomes, as important players in intercellular communication due to their ability to transfer certain molecules to target cells, are believed to take similar effects in promoting bone regeneration with their derived stem cells. Studies have suggested that umbilical cord mesenchymal stem cells (uMSCs) could promote angiogenesis. This study investigated whether exosomes derived from uMSCs (uMSC-Exos) could enhance fracture healing as primary factors by promoting angiogenesis. Materials and methods uMSCs were obtained to isolate uMSC-Exos by ultrafiltration, with exosomes from human embryonic kidney 293 cells (HEK293) and phosphate-buffered saline (PBS) being used as control groups. NanoSight, laser light scattering spectrometer, transmission electron microscopy and Western blotting were used to identify exosomes. Next, uMSC-Exos combined with hydrogel were transplanted into the fracture site in a rat model of femoral fracture. Bone healing processes were monitored and evaluated by radiographic methods on days 7, 14, 21 and 31 after surgery; angiogenesis of the fracture sites was assessed by radiographic and histological strategies on post-operative day 14. In vitro, the expression levels of osteogenesis- or angiogenesis-related genes after being cultured with uMSC-Exos were identified by qRT-PCR. The internalization ability of exosomes was determined using the PKH67 assay. Cell cycle analysis, EdU incorporation and immunofluorescence staining, scratch wound assay and tube formation analysis were also used to determine the altered abilities of human umbilical vein endothelial cells (HUVECs) administered with uMSC-Exos in proliferation, migration and angiogenesis. Finally, to further explore the underlying molecular mechanisms, specific RNA inhibitors or siRNAs were used, and the subsequent effects were observed. Results uMSC-Exos had a diameter of approximately 100 nm, were spherical, meanwhile expressing CD9, CD63 and CD81. Transplantation of uMSC-Exos markedly enhanced angiogenesis and bone healing processes in a rat model of femoral fracture. In vitro, other than enhancing osteogenic differentiation, uMSC-Exos increased the expression of vascular endothelial growth factor (VEGF) and hypoxia inducible factor-1α (HIF-1α). uMSC-Exos were taken up by HUVECs and enhanced their proliferation, migration and tube formation. Finally, by using specific RNA inhibitors or siRNAs, it has been confirmed that HIF-1α played an important role in the uMSC-Exos-induced VEGF expression, pro-angiogenesis and enhanced fracture repair, which may be one of the underlying mechanisms. Conclusions These results revealed a novel role of exosomes in uMSC-mediated therapy and suggested that implanted uMSC-Exos may represent a crucial clinical strategy to accelerate fracture healing via the promotion of angiogenesis. HIF-1α played an important role in this process.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/cpr.12570

Exosomes from human umbilical cord mesenchymal stem cells enhance fracture healing through HIF-1α-mediated promotion of angiogenesis in a rat model of stabilized fracture.

The regeneration of functional tissue in osseous defects is a formidable challenge in orthopedic surgery. In the present study, a novel biomimetic composite scaffold, here called nano-hydroxyapatite (HA)/poly-e-caprolactone (PCL) was fabricated using a selective laser sintering technique. The macrostructure, morphology, and mechanical strength of the scaffolds were characterized. Scanning electronic microscopy (SEM) showed that the nano-HA/PCL scaffolds exhibited predesigned, well-ordered macropores and interconnected micropores. The scaffolds have a range of porosity from 78.54% to 70.31%, and a corresponding compressive strength of 1.38 MPa to 3.17 MPa. Human bone marrow stromal cells were seeded onto the nano-HA/PCL or PCL scaffolds and cultured for 28 days in vitro. As indicated by the level of cell attachment and proliferation, the nano-HA/PCL showed excellent biocompatibility, comparable to that of PCL scaffolds. The hydrophilicity, mineralization, alkaline phosphatase activity, and Alizarin Red S staining indicated that the nano-HA/PCL scaffolds are more bioactive than the PCL scaffolds in vitro. Measurements of recombinant human bone morphogenetic protein-2 (rhBMP-2) release kinetics showed that after nano-HA was added, the material increased the rate of rhBMP-2 release. To investigate the in vivo biocompatibility and osteogenesis of the composite scaffolds, both nano-HA/PCL scaffolds and PCL scaffolds were implanted in rabbit femur defects for 3, 6, and 9 weeks. The wounds were studied radiographically and histologically. The in vivo results showed that both nano-HA/PCL composite scaffolds and PCL scaffolds exhibited good biocompatibility. However, the nano-HA/PCL scaffolds enhanced the efficiency of new bone formation more than PCL scaffolds and fulfilled all the basic requirements of bone tissue engineering scaffolds. Thus, they show large potential for use in orthopedic and reconstructive surgery.

Selective laser sintering fabrication of nano-hydroxyapatite/poly-ε-caprolactone scaffolds for bone tissue engineering applications.

Enhanced bone tissue regeneration by antibacterial and osteoinductive silica-HACC-zein composite scaffolds loaded with rhBMP-2

Repair of large bone defects represents a major challenge for orthopedic surgeons. The newly formed microvessels inside grafts play a crucial role in successful bone tissue engineering. Previously, an active role for mesenchymal stem cell (MSC)-derived exosomes in blood vessel development and progression was suggested in the repair of multiple tissues. However, the reports on the application of MSC-derived exosomes in the repair of large bone defects are sparse. In this study, we encapsulated umbilical MSC-derived exosomes (uMSCEXOs) in hyaluronic acid hydrogel (HA-Gel) and combined them with customized nanohydroxyapatite/poly-e-caprolactone (nHP) scaffolds to repair cranial defects in rats. Imaging and histological evaluation indicated that the uMSCEXOs/Gel/nHP composites markedly enhanced bone regeneration in vivo, and the uMSCEXOs might play a key role in this process. Moreover, the in vitro results demonstrated that uMSCEXOs promoted the proliferation, migration, and angiogenic differentiation of endothelial progenitor cells (EPCs) but did not significantly affect the osteogenic differentiation of BMSCs. Importantly, mechanistic studies revealed that exosomal miR-21 was the potential intercellular messenger that promoted angiogenesis by upregulating the NOTCH1/DLL4 pathway. In conclusion, our findings exhibit a promising exosome-based strategy in repairing large bone defects through enhanced angiogenesis, which potentially regulated by the miR-21/NOTCH1/DLL4 signaling axis.

Umbilical Mesenchymal Stem Cell-Derived Exosome-Encapsulated Hydrogels Accelerate Bone Repair by Enhancing Angiogenesis.

Fabrication of membranes with excellent biocompatibility and bioactivity remains an important technical challenge in bone tissue engineering. In this paper, poly(l-lactic-co-glycolic acid) (PLGA)-SBA15 (Santa Barbara Amorphous 15) composite membranes were prepared by using an electrospinning technique; PLGA was used as a biocompatible and biodegradable polymer and SBA15 was used as a mesoporous silica. The PLGA-SBA15 composite membrane facilitates the cell attachment and the cell proliferation versus pure PLGA membrane where human bone marrow-derived mesenchymal stem cells (hMSCs) were seeded. Furthermore, the analysis of alkaline phosphatase (ALP) activity indicated that this PLGA-SBA15 composite membrane has better osteogenic induction compared with the pure PLGA membrane. Moreover, the presence of SBA15 increased the loading efficiency of the recombinant human bone morphogenetic protein-2 (rhBMP-2) to the membranes. Furthermore, the composite membrane had optimized sustained release of rhBMP-2. Overall, this PLGA-SBA15 composite is an excellent material for bone tissue engineering.

Yan Xia

Papers

Exosomes from human umbilical cord mesenchymal stem cells enhance fracture healing through HIF-1α-mediated promotion of angiogenesis in a rat model of stabilized fracture.

Selective laser sintering fabrication of nano-hydroxyapatite/poly-ε-caprolactone scaffolds for bone tissue engineering applications.

Enhanced bone tissue regeneration by antibacterial and osteoinductive silica-HACC-zein composite scaffolds loaded with rhBMP-2

Umbilical Mesenchymal Stem Cell-Derived Exosome-Encapsulated Hydrogels Accelerate Bone Repair by Enhancing Angiogenesis.

Organic/inorganic composite membranes based on poly(L-lactic-co-glycolic acid) and mesoporous silica for effective bone tissue engineering.