Fabrication of a Cu/Zn co-incorporated calcium phosphate scaffold-derived GDF-5 sustained release system with enhanced angiogenesis and osteogenesis properties

Synthetic scaffolds with multifunctional properties, including angiogenesis and osteogenesis capacities, play an essential role in accelerating bone regeneration. In this study, various concentrations of Cu/Zn ions were incorporated into biphasic calcium phosphate (BCP) scaffolds, and then growth differentiation factor-5 (GDF-5)-loaded poly(lactide-co-glycolide) (PLGA) microspheres were attached onto the ion-doped scaffold. The results demonstrated that with increasing concentration of dopants, the scaffold surface gradually changed from smooth grain crystalline to rough microparticles, and further to a nanoflake film. Additionally, the mass ratio of β-tricalcium phosphate/hydroxyapatite increased with the dopant concentration. Furthermore, GDF-5-loaded PLGA microspheres attached onto the BCP scaffold surface exhibited a sustained release. In vitro co-culture of bone mesenchymal stem cells and vascular endothelial cells showed that the addition of Cu/Zn ions and GDF-5 in the BCP scaffold not only accelerated cell proliferation, but also promoted cell differentiation by enhancing the alkaline phosphatase activity and bone-related gene expression. Moreover, the vascular endothelial growth factor secretion level increased with the dopant concentration, and attained a maximum when GDF-5 was added into the ions-doped scaffold. These findings indicated that BCP scaffold co-doped with Cu/Zn ions exhibited a combined effect of both metal ions, including angiogenic and osteogenic capacities. Moreover, GDF-5 addition further enhanced both the angiogenic and osteogenic capacities of the BCP scaffold. The Cu/Zn co-incorporated BCP scaffold-derived GDF-5 sustained release system produced multifunctional scaffolds with improved angiogenesis and osteogenesis properties.

A Cu/Zn co-incorporated BCP scaffold-derived GDF-5 sustained release system was successfully prepared and exhibited improved angiogenic and osteogenic capacities.     

Osteoinductive 3D scaffolds prepared by blend centrifugal spinning for long-term delivery of osteogenic supplements

Bone regeneration is a long-term process requiring proper scaffolding and drug delivery systems. The current study delivers a three-dimensional (3D) scaffold prepared by blend centrifugal spinning loaded with the osteogenic supplements (OS) β-glycerol phosphate, ascorbate-2-phosphate and dexamethasone. The OS were successfully encapsulated into a fibrous scaffold and showed sustained release for 30 days. Furthermore, biological testing showed the osteoinductive properties of the scaffolds on a model of human mesenchymal stem cells and stimulatory effect on a model of osteoblasts. The osteoinductive properties were further proved in vivo in critical size defects of rabbits. The amount of bone trabecules was bigger compared to control fibers without OS. The results indicate that due to its long-term drug releasing properties, single step fabrication process and 3D structure, the system shows ideal properties for use as a cell-free bone implant in tissue-engineering.

Bone regeneration is a long-term process requiring proper scaffolding and drug delivery systems.     

Biomimetic cellulose/calcium-deficient-hydroxyapatite composite scaffolds fabricated using an electric field for bone tissue engineering

Cellulose has been widely used as micro/nanofibers in various applications of tissue regeneration, but has certain limitations for bone regeneration, e.g., low biocompatibility in inducing osteogenesis. In addition, the low processability from the decomposition property before melting can be a significant obstacle to fabricating a required complex structure through a 3D-printing process. Herein, to overcome the low osteogenic activity of pure cellulose, we suggest a new cellulose-based composite scaffold consisting of cellulose and a high weight fraction (70 wt%) of calcium-deficient-hydroxyapatite (CDHA), which was obtained from the hydrolysis of α-tricalcium phosphate. Using biocompatible components, we fabricated a 3D pore-structure controllable composite scaffold consisting of microfibrous bundles through an electrohydrodynamic printing (EHDP) process supplemented with an ethanol bath. To obtain a mechanically stable and repeatable 3D mesh structure, various process parameters (nozzle-to-target distance, electric field strength, flow rate, and nozzle moving speed) were considered. As a control, a mesh structure fabricated using a normal EHDP process and with a similar pore geometry was used. A variety of cellular responses using preosteoblasts (MC3T3-E1) indicate that a CDHA/cellulose composite scaffold provides an efficient platform for inducing significantly high bone mineralization.

The fabricated ceramic scaffold showed a layer-by-layered mesh structure entangled with cellulose micro/nanofibers and the bioceramic phase. By varying processing parameters, the unique 3D fibrous mesh-structure could be achieved.     

The mineralization,drug release and in vivo bone defect repair properties of calcium phosphates/PLA modified tantalum scaffolds

Calcium phosphate based biomaterials have been widely studied in biomedical areas. Herein, amorphous calcium phosphate (ACP) nanospheres and hydroxyapatite (HA) nanorods were separately prepared and used for coating tantalum (Ta) scaffolds with a polymer of polylactide (PLA). We have found that different crystal phases of calcium phosphate coated on Ta scaffolds displayed different effects on the surface morphologies, mineralization and bovine serum albumin (BSA) release. The ACP-PLA and HA-PLA coated on Ta scaffold were more favorable for in vitro mineralization than bare and PLA coated Ta scaffolds, and resulted in a highly hydrophilic surfaces. Meanwhile, the osteoblast-like cells (MG63) showed favorable properties of adhesion and spreading on both ACP-PLA and HA-PLA coated Ta scaffolds. The ACP-PLA and HA-PLA coated Ta scaffolds showed a high biocompatibility and potential applications for in vivo bone defect repair.

Calcium phosphate modified tantalum scaffolds displayed high performance on mineralization, sustained drug release and in vivo bone defect repair.     

A three-dimensional hydroxyapatite/polyacrylonitrile composite scaffold designed for bone tissue engineering

In recent years, various composite scaffolds based on hydroxyapatite have been developed for bone tissue engineering. However, the poor cell survival micro-environment is still the major problem limiting their practical applications in bone repairing and regeneration. In this study, we fabricated a class of fluffy and porous three-dimensional composite fibrous scaffolds consisting of hydroxyapatite and polyacrylonitrile by employing an improved electrospinning technique combined with a bio-mineralization process. The fluffy structure of the hydroxyapatite/polyacrylonitrile composite scaffold ensured the cells would enter the interior of the scaffold and achieve a three-dimensional cell culture. Bone marrow mesenchymal stem cells were seeded into the scaffolds and cultured for 21 days in vitro to evaluate the response of cellular morphology and biochemical activities. The results indicated that the bone marrow mesenchymal stem cells showed higher degrees of growth, osteogenic differentiation and mineralization than those cultured on the two-dimensional hydroxyapatite/polyacrylonitrile composite membranes. The obtained results strongly supported the fact that the novel three-dimensional fluffy hydroxyapatite/polyacrylonitrile composite scaffold had potential application in the field of bone tissue engineering.

A fluffy and porous (3D) HA composite fibrous scaffold was fabricated by employing an improved electrospinning technique combined with a bio-mineralization process.     

Effects of vitamin D3 release from 3D printed calcium phosphate scaffolds on osteoblast and osteoclast cell proliferation for bone tissue engineering

Vitamin D₃ is a hydrophobic micronutrient and is known for inhibiting osteoclastic bone resorption in vivo via suppression of the Receptor Activator of Nuclear factor-Kappa B (RANK ligand) expression in osteoblasts. Although vitamin D is well-known for its promotion in bone health, little is known on its effects directly on bone cells. The objective of this study was to understand the effects of vitamin D₃ release from 3D printed calcium phosphate scaffolds towards bone cell proliferation. In this study, cholecalciferol, a common intake form of vitamin D₃, was successfully able to release from the scaffold matrix via the use of polyethylene glycol. Results showed a decrease in osteoclast resorption pits and healthier osteoblast cellular morphology compared to the control. Additively manufactured tricalcium phosphate scaffolds with designed porosity were loaded with vitamin D₃ and showed controlled release profiles in phosphate buffer and acetate buffer solutions. The release kinetics of vitamin D₃ from calcium phosphate scaffolds enabling osteoblast proliferation and inhibiting osteoclastic resorption can enhance healing for low load bearing applications for bone defects or permeate voids left by tumor resection.

Release of Vitamin D₃, cholecalciferol, from 3D printed calcium phosphate scaffolds showed reduced osteoclast resorption activity.     

Anisotropic architecture and electrical stimulation enhance neuron cell behaviour on a tough graphene embedded PVA: alginate fibrous scaffold

Tough scaffolds comprised of aligned and conductive fibers are promising for peripheral nerve regeneration due to their unique mechanical and electrical properties. Several studies have confirmed that electrical stimulation can control the axonal extension in vitro. However, the stimulatory effects of scaffold architecture and electrical stimulation have not yet been investigated in detail. Here, we assessed a comparison between aligned and random fibers made of graphene (Gr) embedded sodium alginate (SA) polyvinyl alcohol (PVA) (Gr-AP scaffolds) for peripheral nerve engineering. The effects of applied electrical stimulation and orientation of the fabricated fibers on the in vitro attachment, alignment, and proliferation of PC12 cells (a rat neuronal cell line) were investigated. The results revealed that the aligned fibrous Gr-AP scaffolds closely mimicked the anisotropic structure of the native sciatic nerve. Aligned fibrous Gr-AP scaffolds significantly improved mechanical properties as well as cell-scaffold integration compared to random fibrous scaffolds. In addition, electrical stimulation significantly improved PC12 cell proliferation. In summary, our findings revealed that aligned fibrous Gr-AP scaffolds offered superior mechanical characteristics and structural properties that enhanced neural cell–substrate interactions, resulting in a promising construct for nerve tissue regeneration.

Tough scaffolds comprised of aligned and conductive fibers are promising for peripheral nerve regeneration due to their unique mechanical and electrical properties.     

Moisture affinity of HDPE/phase-change material composites for thermal energy storage applications

Moisture adsoprtion can degrade the structural integrity of thermal energy storage devices and can negatively impact the capacity and charging/discharging behaviour. Steady-state and transient experiments are conducted at various operating temperatures to evaluate the moisture affinity of organic phase-change material (PCM) shape stabilized with high-density polyethylene (HDPE).

A composite HDPE/PCM filament for 3D printing thermal energy storage systems is naturally hydrophobic.     

Fe/Zn-modified tricalcium phosphate (TCP) biomaterials: preparation and biological properties

Bone repairing materials play an essential role in the repair treatment of bone defects. The presence of calcium phosphate invertebrates is of significance for bone repairing processes. However, the mechanical properties and osteogenic activities of many current calcium phosphate materials are not ideal, which limit their biological applications. Therefore, it is an effective alternative strategy to study the modification of calcium phosphate biomaterials to address these limitations. In this research, in order to enhance the biological performance of tricalcium phosphate (β-TCP), metal species (Fe and Zn) modified β-TCP materials through the co-precipitation method were successfully developed. The physical, chemical and biological properties of the binary composites were carefully studied for the first time. The bioactivities of the Fe-TCP and Zn-TCP were evaluated by simulating body fluid (SBF) immersion experiments, blood compatibility, and cytotoxicity tests. The findings demonstrated that the metal-TCP with excellent cytocompatibility and osteogenic properties shows good potential in medical applications.

Fe/Zn-TCP biomaterials were prepared and their bioactivities to enhance the synthetic bone-repair materials were studied in comparison.     

Mineralization of calcium phosphate induced by a silk fibroin film under different biological conditions

Silk fibroin is a promising biomaterial that has been used for tissue engineering applications. However, the influence of silk fibroin on the mineralization of calcium phosphate in different biological environments has not been discussed before. In this work, we fabricated organized silk fibroin film as the organic framework and amorphous calcium phosphate (ACP) deposited on the films as precursors. The transformation pathways and morphology of ACP was then studied in both enzyme and PBS (phosphate buffer saline) solutions. While only hydroxyapatite (HA) crystals formed in enzyme solution, a mixture of tricalcium phosphate (TCP) and HA crystals were obtained in PBS solution, which can be related to the variations of the content of silk fibroin and pH of the solution. Therefore, silk fibroin films can have an important effect on the mineralization process of calcium phosphate in different biological environments. In addition, cell cultivation experiments show that the silk films after mineralization promoted osteogenesis and exhibited good biocompatibility.

Silk fibroin films can have an important effect on the mineralization process of calcium phosphate in different biological environments. There was improvement of MSF with good biocompatibility that are promising in bone tissue engineering.     

Protection of lithium anodes by fibrous silica nanospheres

Lithium metal (anode) has attracted significant attention for use in lithium-metal batteries due to its high energy density, but its practical application is still hindered by the dendrite growth during the battery charging process. Here, fibrous silica nanospheres were prepared via a direct hydrothermal reaction and coated on a separator to form a composite electrode with lithium sheets. Upon using this composite electrode in a symmetrical cell, the charge and discharge curves became more stable and the overpotential was alleviated compared with that of the bare lithium metal electrode. Meanwhile, the coulombic efficiency obtained from the Li‖Cu cell remained above 95.9% after 200 cycles at 0.5 mA h cm⁻². The validity of using this composite electrode in the Li‖LFP (LiFePO₄, lithium iron phosphate) cells was also evaluated. The results show that the composite electrode can help restrict the growth of lithium dendrites and the accumulation of dead lithium.

A fibrous silica nanosphere coating was designed and prepared to protect lithium-metal anodes.     

Ammonium-to-sodium ion-exchange process at the interlayer of octacalcium phosphate

Octacalcium phosphate (OCP) has been considered as the layer component of calcium phosphate, but whether it achieves the ionic-exchange ability of conventional layer components is unclear. As OCP is highly biocompatible, understanding its ionic-exchange properties would potentially expand its pharmaceutical and medical applications. Herein, we demonstrate that the substituted cations in ammonium (NH₄)-substituted octacalcium phosphate (OCP-NH₄) and sodium (Na)-containing ammonium phosphate solutions undergo ion exchanges with OCP interlayers. Replacing NH₄⁺ with Na⁺ did not alter the crystal structure of OCP, confirming that a substituted cation exchange process similar to that in other layered compounds occurs in OCP.

Octacalcium phosphate (OCP) has been considered as the layer component of calcium phosphate, but whether it achieves the ionic-exchange ability of conventional layer components is unclear. In this study, we demonstrated the evidence of ionic exchange process at the interlayer of OCP.     

Chitosan composite scaffolds for articular cartilage defect repair: a review

Articular cartilage (AC) defects lack the ability to self-repair due to their avascular nature and the declined mitotic ability of mature chondrocytes. To date, cartilage tissue engineering using implanted scaffolds containing cells or growth factors is the most promising defect repair method. Scaffolds for cartilage tissue engineering have been comprehensively researched. As a promising scaffold biomaterial for AC defect repair, the properties of chitosan are summarized in this review. Strategies to composite chitosan with other materials, such as polymers (including collagen, gelatin, alginate, silk fibroin, poly-caprolactone, and poly-lactic acid) and bioceramics (including calcium phosphate, calcium polyphosphate, and hydroxyapatite) are presented. Methods to manufacture three-dimensional porous structures to support cell attachment and nutriment exchange have also been included.

Properties of chitosan/polymer and chitosan/bioceramic composite scaffolds for articular cartilage defect repair are reviewed.     

Adsorption of tetracycline antibiotics from an aqueous solution onto graphene oxide/calcium alginate composite fibers

In this study, we report the preparation of a novel environmentally friendly and highly efficient adsorbent, graphene oxide/calcium alginate (GO/CA) composite fibers, via a freeze-drying method using calcium chloride as a cross-linking reagent between graphene oxide and sodium alginate. The maximum tetracycline adsorption capacity of the GO/CA composite fibers predicted by the Langmuir model reached 131.6 mg g⁻¹. The adsorption properties of tetracycline onto the fibers were investigated through several parameters including the solution pH, the adsorbent dose, the initial concentration of tetracycline, and the agitation time. The Langmuir and Freundlich adsorption isotherms were used to investigate the adsorption equilibrium. The kinetics of the adsorption process was predicted using the pseudo-first-order and pseudo-second-order kinetic equations. Furthermore, the mechanism of adsorption was investigated, and it was found that the hydrogen bonding and π–π interaction should serve as predominant contributions to the significantly enhanced adsorption capability.

In this study, we report the preparation of a novel environmentally friendly and highly efficient adsorbent, graphene oxide/calcium alginate (GO/CA) composite fibers, via a freeze-drying method using calcium chloride as a cross-linking reagent between graphene oxide and sodium alginate.     

The facile synthesis and bioactivity of a 3D nanofibrous bioglass scaffold using an amino-modified bacterial cellulose template

Porous bioglass (BG) scaffolds are of great importance in tissue engineering because of their excellent osteogenic properties for bone regeneration. Herein, we reported for the first time the use of amino-modified bacterial cellulose (NBC) as a template to prepare a three-dimensional (3D) nanofibrous BG scaffold by a facile modified sol–gel approach under ultrasonic treatment. The results suggested that the amino groups on the BC template could effectively promote the absorption of the deposited CaO and SiO₂ precursors, and the as-obtained BG scaffold showed a 3D interconnected porous network structure consisting of nanofibers with a diameter of about 20 nm. Furthermore, the as-obtained BG scaffold showed very good bioactivity after being immersed in SBF for 7 days. This research provides a facile and efficient way to prepare a nanofibrous BG scaffold with 3D porous structure, which can be used as a promising candidate for biomedical applications.

A nanofibrous BG scaffold with a high quality 3D porous interconnected structure has been prepared via a facile modified sol–gel approach using amino-modified bacterial cellulose as the template.     

Repair of segmental rabbit radial defects with Cu/Zn co-doped calcium phosphate scaffolds incorporating GDF-5 carrier

Repair of segmental bone defects is a challenge in orthopaedics. A bone substitute is a potential solution for this challenge, and angiogenesis and osteogenesis are critical to the performance of scaffold materials. For enhancing angiogenesis and osteogenesis activities of implanted scaffolds, Cu/Zn co-doped calcium phosphate scaffolds carrying GDF-5-release microspheres were prepared and implanted into surgically created critical-sized rabbit radial defects. Radiological examination, histological analysis and biomechanical tests were used to evaluate the bone healing-union. Results showed that, with increasing Cu/Zn concentrations, new bone area, new blood vessel density, and bending failure load all increased significantly. Furthermore, Cu/Zn co-doped scaffolds incorporating GDF-5-release microspheres exhibited further increased angiogenesis and osteogenesis (vs. Cu/Zn co-doped alone), as well as a superior bending failure load. These show that, simultaneous incorporation of trace essential ions and GDF-5 combines pro-angiogenic and pro-osteogenic actions of these bioactive substances, potentially offering an effective approach to assist the healing of critical-sized bone defects.

Cu/Zn co-doped calcium phosphate scaffolds carrying GDF-5-release microspheres were prepared and implanted into surgically created critical-sized rabbit radial defects.     

Insights into ZnO-based doped porous nanocrystal frameworks

Colloidal nanocrystals play a vital role in several applications. The doping of cations in the nanocrystal matrix enhances the optical, electrical, and magnetic properties. The number and well-defined distribution of the dopant are crucial to protect the nanocrystal from clustering. The XRD, XPS, and XAS instruments reveal the change in the lattice parameters, chemical states, and local coordination environment information. In addition of detecting the position and distribution of the dopant, the 4D-STEM detector mode gathers all types of real-space atomic-resolution images by collecting all diffraction datasets from each electron probe with high-speed and efficient detection. Dopant–host ligand type, reactions conditions, and reaction time optimization during synthesis are critical for the host and dopant reactivity balance. Pearson''s hard/soft acids/bases theory would be a base for balancing the solubility of the dopant–host in the given solvents/surfactant. In addition, tuning the colloidal nanocrystals to secondary structures, which enhances the mass-/ions transport, can contribute a combination of properties that do not exist in the original constituents.

The synthesis of doped nanocomposites under the control of surfactants has outstanding potential for the photocatalytic degradation of dyes and antibacterial activity. 4D-STEM detector mode gathers real-space atomic-resolution images with high-speed and efficient detection.     

Recent developments in the nanomaterial-catalyzed green synthesis of structurally diverse 1,4-dihydropyridines

1,4-Dihydropyridine (1,4-DHP), a privileged heterocyclic scaffold, has been extensively utilized in various biological and therapeutic applications. In this review article, we discussed the role of different nano-catalysts, nanoflakes, nanocomposites, and other green-supported nanomaterials in the synthesis of a biologically active and vital pharmaceutical precursor 1,4-DHP and its derivatives such as polyhydroquinoline, benzopyranopyridines, and dihydropyridine since 2015. It is evident that although the use of various tailored nanostructures under different conditions to optimize the synthesis of 1,4-DHP and its compounds has provided sustainable and efficient proposals, yet the development of greener practices in the synthesis of 1,4-DHPs, which can be applied to design new synthetic routes and sequences in process development, is a far-reaching task to be accomplished.

Single pot multicomponent approaches using different nanomaterials as green catalysts for synthesis of 1,4-dihydropyridine (1,4-DHP), a privileged heterocyclic scaffold with vital biological and therapeutic applications are reviewed.      

Inorganic process for wet silica-doping of calcium phosphate

Silica is not only a biocompatible trace element but also an essential element for bone formation and metabolism. Therefore, it is often doped into bioceramics such as calcium phosphate and calcium carbonate for enhancing biomaterial ability. Heretofore, organic silica materials are employed as silica sources, but the residual organic matter is a significant drawback in biomaterial applications. Therefore, in this study, we introduce a one-pot inorganic synthesis method for the formation of silica-doped octacalcium phosphate (OCP) using Na₂SiO₃ as the silica source. Silica was intercalated into the OCP unit lattice, replacing its hydrous layer structure, and then a layer-by-layer structure of apatite and silica was formed. Furthermore, by immersing the fabricated silica-doped OCP into suitable solutions, both silica-doped hydroxyapatite and carbonate apatite were fabricated through a one-step inorganic processes.

We introduced a one-pot synthesis method for silica doping of calcium phosphate. Silica easily incorporated into OCP interlayer optimizing Na₂SiO₃ concentrations.     

FeCl3 as a low-cost and efficient p-type dopant of Spiro-OMeTAD for high performance perovskite solar cells

Chemical doping is a viable tactic to improve the charge transporting properties of organic semiconductors in efficient perovskite solar cells. In this paper, we first employ the low-cost inorganic salt FeCl₃ as a chemical dopant to replace the traditional expensive cobalt complex for the oxidization of 2,2′,7,7′-tetrakis(N,N-p-dimethoxyphenylamino)-9,9′-spirobifluorene (Spiro-OMeTAD), a typical organic hole-transporter. Based on the joint measurements of electron absorption spectra, cyclic voltammetry, and the hole-only device, we reveal that FeCl₃ can effectively oxidize Spiro-OMeTAD and improve the hole transporting properties of Spiro-OMeTAD. Through carefully optimizing the dopant concentration, solar cells with 80% FeCl₃ doped Spiro-OMeTAD achieve over 17% power conversion efficiency based on a triple cation perovskite photoactive layer, which is comparable to that of devices with a classical cobalt complex dopant. Our work demonstrates the potential of using FeCl₃ as a low-cost chemical dopant for hole-transporting materials in perovskite solar cells.

We have employed low-cost FeCl₃ as efficient dopant of Spiro-OMeTAD for high performance perovskite solar cells.