Versatile-in-All-Trades: Multifunctional Boron-Doped Calcium-Deficient Hydroxyapatite Directs Immunomodulation and Regeneration.

Osseointegration of implants depends on several intertwined factors: osteogenesis, angiogenesis, and immunomodulation. Lately, novel reinforcements allowing faster bonding with osseous tissue have been explored intensively. In this study, we hypothesized the use of boron as a major multifunctional ion to confer versatility to calcium-deficient hydroxyapatite (cHA) synthesized by a wet precipitation/microwave reflux method. By synthesis of boron-doped calcium-deficient hydroxyapatite (BcHA), we expected to obtain an osteoimmunomodulatory and regenerative nanoreinforcement. BcHA was found to possess a pure HA phase, a greater surface area (66.41 m2/g, p = 0.028), and cumulative concentrations of Ca (207.87 ± 6.90 mg/mL, p < 0.001) and B (112.70 ± 11.79 mg/mL, p < 0.001) released in comparison to cHA. Osteogenic potential of BcHA was analyzed using human fetal osteoblasts. BcHA resulted in a drastic increase in the ALP activity (1.11 ± 0.11 mmol/gDNA·min, p < 0.001), biomineralization rate, and osteogenic gene expressions compared to cHA. BcHA angiogenic potential was investigated using human umbilical cord vein endothelial cells. Significantly, the highest VEGF-A release (1111.14 ± 87.82 in 4 h, p = 0.009) and angiogenic gene expressions were obtained for BcHA-treated samples. These samples were also observed to induce a more prominent and highly branched tube network. Finally, inflammatory and inflammasome responses toward BcHA were elucidated using human monocyte-derived macrophages differentiated from THP-1s. BcHA exhibited lower CAS-1 release (50.18 ± 5.52 µg/gDNA µg/gDNA) and higher IL-10 release (126.97 ± 15.05 µg/gDNA) than cHA. In addition, BcHA treatment led to increased expression of regenerative genes such as VEGF-A, RANKL, and BMP-2. In vitro results demonstrated that BcHA has tremendous osteogenic, angiogenic, and immunomodulatory potential to be employed as a "versatile-in-all-trades" modality in various bone tissue engineering applications.

Properties and applications of boron nitride nanotubes.

Nanomaterials have received increasing attention due to their controllable physical and chemical properties and their improved performance over their bulk structures during the last years. Carbon nanostructures are one of the most widely searched materials for use in different applications ranging from electronic to biomedical because of their exceptional physical and chemical properties. However, BN nanostructures surpassed the attention of the carbon-based nanostructure because of their enhanced thermal and chemical stabilities in addition to structural similarity with the carbon nanomaterials. Among these nanostructures, one dimensional-BN nanostructures are on the verge of development as new materials to fulfill some necessities for different application areas based on their excellent and unique properties including their tunable surface and bandgap, electronic, optical, mechanical, thermal, and chemical stability. Synthesis of high-quality boron nitride nanotubes (BNNTs) in large quantities with novel techniques provided greater access, and increased their potential use in nanocomposites, biomedical fields, and nanodevices as well as hydrogen uptake applications. In this review, properties and applications of one-dimensional BN (1D) nanotubes, nanofibers, and nanorods in hydrogen uptake, biomedical field, and nanodevices are discussed in depth. Additionally, research on native and modified forms of BNNTs and also their composites with different materials to further improve electronic, optical, structural, mechanical, chemical, and biological properties are also reviewed. BNNTs find many applications in different areas, however, they still need to be further studied for improving the synthesis methods and finding new possible future applications.

Multifunctional natural polymer-based metallic implant surface modifications.

High energy traumas could cause critical damage to bone, which will require permanent implants to recover while functionally integrating with the host bone. Critical sized bone defects necessitate the use of bioactive metallic implants. Because of bioinertness, various methods involving surface modifications such as surface treatments, the development of novel alloys, bioceramic/bioglass coatings, and biofunctional molecule grafting have been utilized to effectively integrate metallic implants with a living bone. However, the applications of these methods demonstrated a need for an interphase layer improving bone-making to overcome two major risk factors: aseptic loosening and peri-implantitis. To accomplish a biologically functional bridge with the host to prevent loosening, regenerative cues, osteoimmunomodulatory modifications, and electrochemically resistant layers against corrosion appeared as imperative reinforcements. In addition, interphases carrying antibacterial cargo were proven to be successful against peri-implantitis. In the literature, metallic implant coatings employing natural polymers as the main matrix were presented as bioactive interphases, enabling rapid, robust, and functional osseointegration with the host bone. However, a comprehensive review of natural polymer coatings, bridging and grafting on metallic implants, and their activities has not been reported. In this review, state-of-the-art studies on multifunctional natural polymer-based implant coatings effectively utilized as a bone tissue engineering (BTE) modality are depicted. Protein-based, polysaccharide-based coatings and their combinations to achieve better osseointegration via the formation of an extracellular matrix-like (ECM-like) interphase with gap filling and corrosion resistance abilities are discussed in detail. The hypotheses and results of these studies are examined and criticized, and the potential future prospects of multifunctional coatings are also proposed as final remarks.

Boron-doped Biphasic Hydroxyapatite/ß-Tricalcium Phosphate for Bone Tissue Engineering.

Boron-doped hydroxyapatite/tricalcium phosphates (BHTs) were synthesized to study boron uptake and correlate structural alterations of incremental boron addition (0 to 10 mol%). BHTs with a Ca/P ratio of 1.6 were prepared by a wet precipitation/microwave reflux method, sieved (< 70 µm) and characterized. XRD and FTIR analyses revealed that boron slightly distorted apatite crystal, increased crystallinity (95.78 ± 2.08% for 5BHT) and crystallite size (103.39 ± 23.47 nm for 5BHT) and still, boron addition did not show any further detrimental effects. Total surface area (4.05 ± 0.82 m2/g for 10BHT) and mesoporosity (23.90 ± 7.92 µL/g for 10BHT) were expanded as boron content was increased. Moreover, boron addition made grains become smaller (0.21 ± 0.06 µm for 5BHT) and ordered while hardness (10.51 ± 0.86 GPa for 10BHT) increased. Boron incorporation enhanced bioactivity with significantly highest calcium phosphate deposition and protein adsorption (135.29 ± 29.58 µg on 10BHT). In return, boron favored highest alkaline phosphatase activity (4.80 ± 0.40 MALP/ngDNA.min), intracellular calcium (23.61 ± 0.68 g/gDNA), phosphate (31.84 ± 4.68 g/gDNA), and protein (23.70 ± 3.46 g/gDNA) storage in 5BHT without cytotoxicity (128 ± 18% viability compared to pure HT). Compared to literature, it can be pointed out that we successfully employed an optimal procedure for production of BHTs and incorporated significantly higher boron content in HT (5.23 mol%). Additionally, results tended to conclude that 5BHT samples (5 mol% boron in HT) demonstrated a very high potential to be used in composite bone tissue constructs.

Composite clinoptilolite/PCL-PEG-PCL scaffolds for bone regeneration: In vitro and in vivo evaluation.

In this study, clinoptilolite (CLN) was employed as a reinforcement in a polymer-based composite scaffold in bone tissue engineering and evaluated in vivo for the first time. Highly porous, mechanically stable, and osteogenic CLN/PCL-PEG-PCL (CLN/PCEC) scaffolds were fabricated with modified particulate leaching/compression molding technique with varying CLN contents. We hypothesized that CLN reinforcement in a composite scaffold will improve bone regeneration and promote repair. Therefore, the scaffolds were analyzed for compressive strength, biodegradation, biocompatibility, and induction of osteogenic differentiation in vitro. CLN inclusion in PC-10 (10% w/w) and PC-20 (20% w/w) scaffolds revealed 54.7% and 53.4% porosity, higher dry (0.62 and 0.76 MPa), and wet (0.37 and 0.45 MPa) compressive strength, greater cellular adhesion, alkaline phosphatase activity (2.20 and 2.82 mg/gDNA /min), and intracellular calcium concentration (122.44 and 243.24 g Ca/mgDNA ). The scaffolds were evaluated in a unicortical bone defect at anterior aspect of proximal tibia of adult rabbits 4 and 8 weeks postimplantation. Similar to in vitro results, CLN-containing scaffolds led to efficient regeneration of bone in a dose-dependent manner. PC-20 demonstrated highest quality of bone union, cortex development, and bone-scaffold interaction at the defect site. Therefore, higher CLN content in PC-20 permitted robust remodeling whereas pure PCEC (PC-0) scaffolds displayed fibrous tissue formation. Consequently, CLN was proven to be a potent reinforcement in terms of promoting mechanical, physical, and biological properties of polymer-based scaffolds in a more economical, easy-to-handle, and reproducible approach.

Porous clinoptilolite-nano biphasic calcium phosphate scaffolds loaded with human dental pulp stem cells for load bearing orthopedic applications.

Clinoptilolite (Cpt)-nanohydroxyapatite (HA) (Cpt-HA) scaffolds were fabricated as a potential material for loadbearing orthopaedic applications. Cpt-HA materials were successfully synthesized by using microwave assisted reflux method followed by the fabrication of three-dimensional (3D) porous scaffold via thermal decomposition process using polyethylene glycol (PEG)/ polyvinyl alcohol (PVA) as porogens. The scaffold materials were characterized using x-ray diffraction, Fourier transform Infra-red, Scanning electron microscopy and Energy dispersive spectroscopy techniques. Incorporation of Cpt in HA scaffold significantly increased the compressive strength and surface hardness while scaffolds retained an interconnected porous structure with 64% porosity. Human dental pulp stem cells (DPSCs) were isolated from the third molar and used as pluripotent-like cell model to evaluate the biological properties of Cpt-HA scaffolds. Highest cellular attachment and proliferation were observed for DPSCs seeded on 2.0 g Cpt-HA scaffolds compare to pure HA. Similarly, significantly higher ALP activity of cells was observed on Cpt-HA scaffolds compared to pure HA. The enhanced proliferation and osteogenic response of the DPSCs cultured on Cpt-HA scaffolds suggest that the fabricated scaffolds can be used in bone tissue engineering. In this work, we have successfully shown that the interconnected porous Cpt-HA scaffolds have superior mechanical biological properties compared to pure HA scaffold.

Resorbable PCEC/gelatin-bismuth doped bioglass-graphene oxide bilayer membranes for guided bone regeneration.

Guided bone regeneration (GBR) is a therapeutic modality applied prior to dental implant placement to increase bone density at the defect site or during placement for directing bone growth around implant. In this study, an asymmetric, bilayer structure was prepared by covalently bonding a dense polycaprolactone-polyethylene glycol-polycaprolactone (PCEC) membrane layer with a hydrogel layer composed of bismuth doped bioactive glass (BG, 45S5) and graphene oxide (GO) particles incorporated in gelatin. Structural and mechanical properties (surface morphology and chemistry, thickness, degradation rate and tensile strength of GBR membranes) were studied. Membranes had a 3D structure having almost 1 mm thickness which is suitable for space filling. Highest tensile strength (TS) (1.71 ± 0.10 MPa, p < 0.001) was observed for membranes having the highest BG containing group (BG20) while lowest TS was observed (1.23 ± 0.11 MPa, p < 0.001) for BG8/GO2 samples. Similarly, hydrolytic degradation of BG20 involving bilayer structures was slower in phosphate buffered saline (PBS) (23% ± 5% in 4 weeks) than other GBR membranes while biodegraded at an equal rate in lipase (BG20 as 72% ± 3%, BG10 as 69% ± 1%, BG8/GO2 as 71% ± 7% and BG2/GO8 as 74% ± 8%). BG8/GO2, displayed lowest gelatin (GEL) release in PBS over 28 d period (175% ± 9% and 164% ± 10% mgGEL/gsample, p < 0.001). However, all bilayer membranes displayed a similar rate of degradation in lipase solution and also had similar mineral deposition ability in simulated body fluid. Significantly higher cell proliferation (p < 0.001) and osteogenic differentiation (p < 0.001) of human dental pulp stem cells were observed in BG20 and BG10 membrane groups than all other groups. On the other hand, GO presence decreased both mechanical and osteoinductive properties compared to pure BG counterparts. Collectively, amine introduced (aminolysis) synthetic dense PCEC layer was covalently bonded to composite hydrogel layer to obtain coherent bilayer membranes for GBR. They were successfully produced to have two layers designed to prevent fibrous tissue movement towards bone defect while enabling bone regeneration. BG20 membrane groups demonstrated higher calcium phosphate deposition TS, cellular growth and osteogenic differentiation.