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Background: Replacement of diseased areas of the joint with tissue-engineered osteochondral grafts has shown potential in the treatment of osteoarthritis. Bioactive glasses are candidates for the osseous analog of these grafts.Questions/purposes: (1) Does Bioactive Glass 13-93 (BG 13-93) as a subchondral substrate improve collagen and glycosaminoglycan production in a tissue-engineered cartilage layer? (2) Does BG 13-93 as a culture medium supplement increase the collagen and glycosaminoglycan production and improve the mechanical properties in a tissue-engineered cartilage layer?Methods: In Study 1, bioactive glass samples (n = 4) were attached to a chondrocyte-seeded agarose layer to form an osteochondral construct, cultured for 6 weeks, and compared to controls. In Study 2, bioactive glass samples (n = 5) were cocultured with cell-seeded agarose for 6 weeks. The cell-seeded agarose layer was exposed to BG 13-93 either continuously or for the first or last 2 weeks in culture or had no exposure.Results: Osteochondral constructs with a BG 13-93 base had improved glycosaminoglycan deposition but less collagen II content. Agarose scaffolds that had a temporal exposure to BG 13-93 within the culture medium had improved mechanical and biochemical properties compared to continuous or no exposure.Conclusions: When used as a subchondral substrate, BG 13-93 did not improve biochemical properties compared to controls. However, as a culture medium supplement, BG 13-93 improved the biochemical and mechanical properties of a tissue-engineered cartilage layer.Clinical Relevance: BG 13-93 may not be suitable in osteochondral constructs but could have potential as a medium supplement for neocartilage formation. [ABSTRACT FROM AUTHOR]

Total hip arthroplasty (THA) bearings were fabricated from silicon nitride (Si(3)N(4)) powder. Mechanical testing showed that Si(3)N(4) had improved fracture toughness and fracture strength over modern alumina (Al(2)O(3)) ceramic. When tested with Si(3)N(4) cups in a hip simulator, both cobalt-chromium (CoCr) and Si(3)N(4) femoral heads produced low wear rates that were comparable to Al(2)O(3)-Al(2)O(3) bearings in THA. This study offers experimental support for a novel metal-ceramic THA bearing couple that combines the reliability of CoCr femoral heads with the wear advantages of ceramic surfaces. [ABSTRACT FROM AUTHOR]

Bone cement is used extensively in orthopedics to anchor prostheses to bone and fill voids. Incorporating bioactive glass into poly(methyl methacrylate) (PMMA)-based bone cement could potentially improve its effectiveness for these tasks. This study characterizes the mechanical and degradation properties of composites containing PMMA-based bone cement and particles of borate bioactive glass designated as 13-93B3. Glass particles of size 5, 33, and 100 μm were mixed with PMMA bone cement to create composites containing 20, 30, and 40 wt % glass. Composites and a bone cement control were soaked in phosphate-buffered saline. Compressive strength, Young's modulus, weight loss, water uptake, solution pH, and ionic concentrations were measured over 21 days. The compressive strengths of composites decreased over 21 days. Average Young's moduli of the composites remained below 3 GPa. Weight loss and water uptake of specimens did not exceed 2 and 6%, respectively. Boron concentrations and pH of all solutions increased over time, with higher glass weight fractions leading to higher pH values. Results demonstrated that the composite can sustain glass degradation and ionic release without compromising short-term mechanical strength., (© 2020 Wiley Periodicals, Inc.)

Our aims were to 1) evaluate the capacity of hollow hydroxyapatite (HA) microspheres (212-250 μm) to serve as a delivery system for controlled release of BMP-2 in vitro and 2) examine relaxin as an enhancer of BMP-2 for bone regeneration. Hollow HA microspheres were converted from borate glass microspheres and characterized using X-ray diffraction, Fourier-transform infrared spectroscopy, scanning electron microscopy, and the Brunauer-Emmett-Teller method. The microspheres loaded with BMP-2 and relaxin were implanted for 6 weeks in Sprague Dawley rats with calvarial defects. BMP-2 alone in the range up to 1 μg per defect exhibited dose-dependent bone regeneration while relaxin alone in the range up to 0.25 μg per defect did not promote bone regeneration. When compared with BMP-2 alone (1 μg per defect), a 50% reduction in the BMP-2 dose was achieved with the addition of 0.05, 0.1, or 0.25 μg of relaxin per defect. These results show that loading HA microspheres with a combination of relaxin and BMP-2 can significantly reduce the BMP-2 dose required to regenerate an equivalent amount of bone., (© 2020 Wiley Periodicals, Inc.)

Borate bioactive glass 13-93B3 converts into an osteoconductive hydroxyapatite-like material in a liquid medium. In this study, 13-93B3 was incorporated into a commercial PMMA (poly(methyl methacrylate)) bone cement, and the conversion of the glass into a precipitate in solution was investigated with scanning electron microscopy, energy dispersive X-ray spectroscopy, Fourier transform infrared (spectroscopy)-attenuated total reflection, and micro-Raman spectroscopy. Glass particles of 5, 33, and 100 μm diameter were each mixed with the PMMA cement to create 20, 30, and 40% glass-loaded composites. Precipitate formation was found to be a calcium-deficient apatite partially substituted with magnesium ions that resembles native bone material and would ideally encourage bone growth better than stoichiometric hydroxyapatite. Composites of bone cement and 13-93B3 show promise as a means of encouraging bone attachment to the surface of the bone cement., (© 2019 Wiley Periodicals, Inc.)

There is a need for synthetic grafts to reconstruct large bone defects using minimal invasive surgery. Our previous study showed that incorporation of Sr into bioactive borate glass cement enhanced the osteogenic capacity in vivo . However, the amount of Sr in the cement to provide an optimal combination of physicochemical properties and capacity to stimulate bone regeneration and the underlying molecular mechanism of this stimulation is yet to be determined. In this study, bone cements composed of bioactive borosilicate glass particles substituted with varying amounts of Sr (0 mol% to 12 mol% SrO) were created and evaluated in vitro and in vivo . The setting time of the cement increased with Sr substitution of the glass. Upon immersion in PBS, the cement degraded and converted more slowly to HA (hydroxyapatite) with increasing Sr substitution. The released Sr 2+ modulated the proliferation, differentiation, and mineralization of hBMSCs (human bone marrow mesenchymal stem cells) in vitro . Osteogenic characteristics were optimally enhanced with cement (designated BG6Sr) composed of particles substituted with 6mol% SrO. When implanted in rabbit femoral condyle defects, BG6Sr cement supported better peri-implant bone formation and bone-implant contact, comparing to cements substituted with 0mol% or 9mol% SrO. The underlying mechanism is involved in the activation of Wnt/β-catenin signaling pathway in osteogenic differentiation of hBMSCs. These results indicate that BG6Sr cement has a promising combination of physicochemical properties and biological performance for minimally invasive healing of bone defects., Competing Interests: The authors declared that they have no conflicts of interest to this work., (© 2020 Production and hosting by Elsevier B.V. on behalf of KeAi Communications Co., Ltd.)

Introduction: Local delivery of antibiotics using bone cement as the delivery vehicle is an established method of managing implant-associated orthopedic infections. Various fillers have been added to cement to increase antibiotic elution, but they often do so at the expense of strength. This study evaluated the effect of adding a borate bioactive glass, previously shown to promote bone formation, on vancomycin elution from PMMA bone cement. Methods: Five cement composites were made: three loaded with borate bioactive glass along with 0, 1, and 5 grams of vancomycin and two without any glass but with 1 and 5 grams vancomycin to serve as controls. The specimens were soaked in PBS. Eluate of vancomycin was collected every 24 hours and analyzed by HPLC. Orthopedic-relevant mechanical properties of each composite were tested over time. Results: The addition of borate bioactive glass provided an increase in vancomycin release at Day 1 and an increase in sustained vancomycin release throughout the treatment period. An 87.6% and 21.1% increase in cumulative vancomycin release was seen for both 1g and 5g loading groups, respectively. Compressive strength of all composites remained above the weight-bearing threshold of 70 MPa throughout the duration of the study with the glass-containing composites showing comparable strength to their respective controls. Conclusion: The incorporation of borate bioactive glass into commercial PMMA bone cement can significantly increase the elution of vancomycin. The mechanical strength of the cement-glass composites remained above 70 MPa even after soaking for 8 weeks, suggesting their suitability for orthopedic weight-bearing applications., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Bioactive glass scaffolds have been used to heal small contained bone defects but their application to repairing structural bone is limited by concerns about their mechanical reliability. In the present study, the addition of an adherent polymer layer to the external surface of strong porous bioactive glass (13-93) scaffolds was investigated to improve their toughness. Finite element modeling (FEM) of the flexural mechanical response of beams composed of a porous glass and an adherent polymer layer predicted a reduction in the tensile stress in the glass with increasing thickness and elastic modulus of the polymer layer. Mechanical testing of composites with structures similar to the models, formed from 13-93 glass and polylactic acid (PLA), showed trends predicted by the FEM simulations but the observed effects were considerably more dramatic. A PLA layer of thickness -400 µm, equal to -12.5% of the scaffold thickness, increased the load-bearing capacity of the scaffold in four-point bending by ~50%. The work of fracture increased by more than 10,000%, resulting in a non-brittle mechanical response. These bioactive glass-PLA composites, combining bioactivity, high strength, high work of fracture and an internal architecture shown to be conducive to bone infiltration, could provide optimal implants for healing structural bone defects.

Although poly(methylmethacrylate) (PMMA) cements are widely used in orthopaedics, they have numerous drawbacks. This study aimed to improve their bioactivity and osseointegration by incorporating strontium-containing borate bioactive glass (SrBG) as the reinforcement phase and bioactive filler of PMMA cement. The prepared SrBG/PMMA composite cements showed significantly decreased polymerization temperature when compared with PMMA and retained properties of appropriate setting time and high mechanical strength. The bioactivity of SrBG/PMMA composite cements was confirmed in vitro , evidenced by ion release (Ca, P, B and Sr) from SrBG particles. The cellular responses of MC3T3-E1 cells in vitro demonstrated that SrBG incorporation could promote adhesion, migration, proliferation and collagen secretion of cells. Furthermore, our in vivo investigation revealed that SrBG/PMMA composite cements presented better osseointegration than PMMA bone cement. SrBG in the composite cement could stimulate new-bone formation around the interface between the composite cement and host bone at eight and 12 weeks post-implantation, whereas PMMA bone cement only stimulated development of an intervening connective tissue layer. Consequently, the SrBG/PMMA composite cement may be a better alternative to PMMA cement in clinical applications and has promising orthopaedic applications by minimal invasive surgery., (© 2017 The Author(s).)

There is a need for synthetic biomaterials to heal bone defects using minimal invasive surgery. In the present study, an injectable cement composed of bioactive borate glass particles and a chitosan bonding solution was developed and evaluated for its capacity to heal bone defects in a rabbit femoral condyle model. The injectability and setting time of the cement in vitro decreased but the compressive strength increased (8±2MPa to 31±2MPa) as the ratio of glass particles to chitosan solution increased (from 1.0gml -1 to 2.5gml -1 ). Upon immersing the cement in phosphate-buffered saline, the glass particles reacted and converted to hydroxyapatite, imparting bioactivity to the cement. Osteoblastic MC3T3-E1 cells showed enhanced proliferation and alkaline phosphatase activity when incubated in media containing the soluble ionic product of the cement. The bioactive glass cement showed a better capacity to stimulate bone formation in rabbit femoral condyle defects at 12weeks postimplantation when compared to a commercial calcium sulfate cement. The injectable bioactive borate glass cement developed in this study could provide a promising biomaterial to heal bone defects by minimal invasive surgery., (Copyright © 2016 Elsevier B.V. All rights reserved.)

There is a clinical need for synthetic bioactive materials that can reliably repair intercalary skeletal tissue loss in load-bearing bones. Bioactive glasses have been investigated as one such material but their mechanical response has been a concern. Previously, we created bioactive silicate glass (13-93) scaffolds with a uniform grid-like microstructure which showed a compressive strength comparable to human cortical bone but a much lower flexural strength. In the present study, finite element modeling (FEM) was used to re-design the scaffold microstructure to improve its flexural strength without significantly lowering its compressive strength and ability to support bone infiltration in vivo. Then scaffolds with the requisite microstructures were created by a robotic deposition method and tested in four-point bending and compression to validate the FEM simulations. In general, the data validated the predictions of the FEM simulations. Scaffolds with a porosity gradient, composed of a less porous outer region and a more porous inner region, showed a flexural strength (34±5MPa) that was more than twice the value for the uniform grid-like microstructure (15±5MPa) and a higher compressive strength (88±20MPa) than the grid-like microstructure (72±10MPa). Upon implantation of the scaffolds for 12weeks in rat calvarial defects in vivo, the amount of new bone that infiltrated the pore space of the scaffolds with the porosity gradient (37±16%) was similar to that for the grid-like scaffolds (35±6%). These scaffolds with a porosity gradient that better mimics the microstructure of human long bone could provide more reliable implants for structural bone repair., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The release of inorganic ions from biomaterials could provide an alternative approach to the use of growth factors for improving tissue healing. In the present study, the release of copper (Cu) ions from bioactive silicate (13-93) glass scaffolds on the response of cells in vitro and on bone regeneration and angiogenesis in vivo was studied. Scaffolds doped with varying concentrations of Cu (0-2.0wt.% CuO) were created with a grid-like microstructure by robotic deposition. When immersed in simulated body fluid in vitro, the Cu-doped scaffolds released Cu ions into the medium in a dose-dependent manner and converted partially to hydroxyapatite. The proliferation and alkaline phosphatase activity of pre-osteoblastic MC3T3-E1 cells cultured on the scaffolds were not affected by 0.4 and 0.8wt.% CuO in the glass but they were significantly reduced by 2.0wt.% CuO. The percent new bone that infiltrated the scaffolds implanted for 6weeks in rat calvarial defects (46±8%) was not significantly affected by 0.4 or 0.8wt.% CuO in the glass whereas it was significantly inhibited (0.8±0.7%) in the scaffolds doped with 2.0wt.% CuO. The area of new blood vessels in the fibrous tissue that infiltrated the scaffolds increased with CuO content of the glass and was significantly higher for the scaffolds doped with 2.0wt.% CuO. Loading the scaffolds with bone morphogenetic protein-2 (1μg/defect) significantly enhanced bone infiltration and reduced fibrous tissue in the scaffolds. These results showed that doping the 13-93 glass scaffolds with up to 0.8wt.% CuO did not affect their biocompatibility whereas 2.0wt.% CuO was toxic to cells and detrimental to bone regeneration., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Hollow hydroxyapatite (HA) microspheres, with a high-surface-area mesoporous shell, can provide a unique bioactive and osteoconductive carrier for proteins to stimulate bone regeneration. However, synthetic HA has a slow resorption rate and a limited ability to remodel into bone. In the present study, hollow HA microspheres with controllable amounts of carbonate substitution (0-12 wt.%) were created using a novel glass conversion route and evaluated in vitro and in vivo. Hollow HA microspheres with ~12 wt.% of carbonate (designated CHA12) showed a higher surface area (236 m(2) g(-1)) than conventional hollow HA microspheres (179 m(2)g(-1)) and a faster degradation rate in a potassium acetate buffer solution. When implanted for 12 weeks in rat calvarial defects, the CHA12 and HA microspheres showed a limited capacity to regenerate bone but the CHA12 microspheres resorbed faster than the HA microspheres. Loading the microspheres with bone morphogenetic protein-2 (BMP2) (1 μg per defect) stimulated bone regeneration and accelerated resorption of the CHA12 microspheres. At 12 weeks, the amount of new bone in the defects implanted with the CHA12 microspheres (73±8%) was significantly higher than the HA microspheres (59±2%) while the amount of residual CHA12 microspheres (7±2% of the total defect area) was significantly lower than the HA microspheres (21±3%). The combination of these carbonate-substituted HA microspheres with clinically safe doses of BMP2 could provide promising implants for healing non-loaded bone defects., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Copper doped borosilicate glasses (BG-Cu) were studied by means of FT-IR, Raman, UV-vis and NMR spectroscopies to investigate the changes that appeared in the structure of borosilicate glass matrix by doping copper ions. Micro-fil and immunohistochemistry analysis were applied to study the angiogenesis of its derived scaffolds in vivo. Results indicated that the Cu ions significantly increased the B-O bond of BO4 groups at 980 cm(-1), while they decrease that of BO2O(-) groups at 1440-1470 cm(-1) as shown by Raman spectra. A negative shift was observed from (11)B and (29)Si NMR spectra. The (11)B NMR spectra exhibited a clear transformation from BO3 into BO4 groups, caused by the agglutination effect of the Cu ions and the charge balance of the agglomerate in the glass network, leading to a more stable glass network and lower ions release rate in the degradation process. Furthermore, the BG-Cu scaffolds significantly enhanced blood vessel formation in rat calvarial defects at 8 weeks post-implantation. Generally, it suggested that the introduction of Cu into borosilicate glass endowed glass and its derived scaffolds with good properties, and the cooperation of Cu with bioactive glass may pave a new way for tissue engineering., (Copyright © 2015 Elsevier B.V. All rights reserved.)

There is growing interest in biomaterials that can cure bone infection and also regenerate bone. In this study, two groups of implants composed of 10% (wt/wt) teicoplanin (TEC)-loaded borate bioactive glass (designated TBG) or calcium sulfate (TCS) were created and evaluated for their ability to release TEC in vitro and to cure methicillin-resistant Staphylococcus aureus (MRSA)-induced osteomyelitis in a rabbit model. When immersed in phosphate-buffered saline (PBS), both groups of implants provided a sustained release of TEC at a therapeutic level for up to 3 to 4 weeks while they were gradually degraded and converted to hydroxyapatite. The TBG implants showed a longer duration of TEC release and better retention of strength as a function of immersion time in PBS. Infected rabbit tibiae were treated by debridement, followed by implantation of TBG or TCS pellets or intravenous injection with TEC, or were left untreated. Evaluation at 6 weeks postimplantation showed that the animals implanted with TBG or TCS pellets had significantly lower radiological and histological scores, lower rates of MRSA-positive cultures, and lower bacterial loads than those preoperatively and those of animals treated intravenously. The level of bone regeneration was also higher in the defects treated with the TBG pellets. The results showed that local TEC delivery was more effective than intravenous administration for the treatment of MRSA-induced osteomyelitis. Borate glass has the advantages of better mechanical strength, more desirable kinetics of release of TEC, and a higher osteogenic capacity and thus could be an effective alternative to calcium sulfate for local delivery of TEC., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

Silicon nitride (Si3N4) has a distinctive combination of material properties such as high strength and fracture toughness, inherent phase stability, scratch resistance, low wear, biocompatibility, hydrophilic behavior, excellent radiographic imaging and resistance to bacterial adhesion, all of which make it an attractive choice for orthopaedic implants. Unlike oxide ceramics, the surface chemistry and topography of Si3N4 can be engineered to address potential in vivo needs. Morphologically, it can be manufactured to have an ultra-smooth or highly fibrous surface structure. Its chemistry can be varied from that of a silica-like surface to one which is predominately comprised of silicon-amines. In the present study, a Si3N4 bioceramic was subjected to thermal, chemical, and mechanical treatments in order to induce changes in surface composition and features. The treatments included grinding and polishing, etching in aqueous hydrofluoric acid, and heating in nitrogen or air. The treated surfaces were characterized using a variety of microscopy techniques to assess morphology. Surface chemistry and phase composition were determined using X-ray photoelectron and Raman spectroscopy, respectively. Streaming potential measurements evaluated surface charging, and sessile water drop techniques assessed wetting behavior. These treatments yielded significant differences in surface properties with isoelectric points ranging from 2 to 5.6, and moderate to extremely hydrophilic water contact angles from ∼65° to ∼8°. This work provides a basis for future in vitro and in vivo studies which will examine the effects of these treatments on important orthopaedic properties such as friction, wear, protein adsorption, bacteriostasis and osseointegration., Statement of Significance: Silicon nitride (Si3N4) exhibits a unique combination of bulk mechanical and surface chemical properties that make it an ideal biomaterial for orthopaedic implants. It is already being used for interbody spinal fusion cages and is being developed for total joint arthroplasty. Its surface texture and chemistry are both highly tunable, yielding physicochemical combinations that may lead to enhanced osseointegration and bacterial resistance without compromising bulk mechanical properties. This study demonstrates the ease with which significant changes to Si3N4's surface phase composition, charging, and wetting behavior can be induced, and represents an initial step towards a mechanistic understanding of the interaction between implant surfaces and the biologic environment., (Copyright © 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Multifunctional biocompatible scaffolds with enhanced osteogenic capacity coupled with magnetic and magnetothermal properties are of great interest for the repair of large bone defects resulting from the resection of tumors. In the present study, we created borosilicate bioactive glass (BG) scaffolds loaded with varying amounts (5-15 wt%) of Fe 3 O 4 magnetic nanoparticles (MNPs) and evaluated their performance in vitro and in vivo. The incorporation of MNPs endowed scaffolds with excellent magnetic, controlled magnetothermal properties and higher mechanical capacity. The MNP-loaded scaffolds were not toxic to human bone marrow-derived stem cells (hBMSCs) cultured on the scaffolds in vitro. The alkaline phosphatase activity and the osteogenic gene expression of the hBMSCs increased with increasing amount of MNPs in the scaffolds. When implanted in rat calvarial defects for 8 weeks, the scaffolds loaded with 15 wt% MNPs showed a significantly better capacity to regenerate bone when compared to the scaffolds without the MNPs. These MNP-loaded BG scaffolds are promising implants for regenerating bone in defects resulting from tumor resection.

The biomaterials with high osteogenic ability are being intensively investigated. In this study, we evaluated the bioactivity and osteogenesis of BG-Zn scaffolds in vitro and in vivo with a rodent calvarial defects model. Zinc containing borosilicate bioactive glass was prepared by doping glass with 1.5, 5 and 10 wt.% ZnO (denoted as BG-1.5Zn, BG-5Zn and BG-10Zn, respectively). When immersed in simulated body fluid, dopant ZnO retarded the degradation process, but did not affect the formation of hydroxyapatite (HA) after long-period soaking. BG-Zn scaffolds showed controlled release of Zn ions into the medium for over 8 weeks. Human bone marrow derived stem cells (hBMSCs) attached well on the BG-1.5Zn and BG-5Zn scaffolds, which exhibited no cytotoxicity to hBMSCs. In addition, the alkaline phosphatase activity of the hBMSCs increased with increasing dopant amount in the glass, while the BG-10Zn group showed over-dose of Zn. Furthermore, when implanted in rat calvarial defects for 8 weeks, the BG-5Zn scaffolds showed a significantly better capacity to regenerate bone tissue compared to the non-doping scaffolds. Generally, these results showed the BG-Zn scaffolds with high osteogenic capacity will be promising candidates using in bone tissue repair and regeneration., (Copyright © 2015. Published by Elsevier B.V.)

There is growing interest in the use of synthetic biomaterials to deliver inorganic ions that are known to stimulate angiogenesis and osteogenesis in vivo. In the present study, we investigated the effects of varying amounts of copper in a bioactive glass on the response of human bone marrow-derived mesenchymal stem cells (hBMSCs) in vitro and on blood vessel formation and bone regeneration in rat calvarial defects in vivo. Porous scaffolds of a borosilicate bioactive glass (composition 6Na2O, 8K2O, 8MgO, 22CaO, 36B2O3, 18SiO2, 2P2O5, mol.%) doped with 0.5, 1.0 and 3.0wt.% CuO were created using a foam replication method. When immersed in simulated body fluid, the scaffolds released Cu ions into the medium and converted to hydroxyapatite. At the concentrations used, the Cu in the glass was not toxic to the hBMSCs cultured on the scaffolds in vitro. The alkaline phosphatase activity of the hBMSCs and the expression levels of angiogenic-related genes (vascular endothelial growth factor and basic fibroblast growth factor) and osteogenic-related genes (runt-related transcription factor 2, bone morphogenetic protein-2 and osteopontin) increased significantly with increasing amount of Cu in the glass. When implanted in rat calvarial defects in vivo, the scaffolds (3wt.% CuO) significantly enhanced both blood vessel formation and bone regeneration in the defects at 8weeks post-implantation. These results show that doping bioactive glass implants with Cu is a promising approach for enhancing angiogenesis and osteogenesis in the healing of osseous defects., (Copyright © 2014 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Native porcine nucleus pulposus (NP) tissue harbors a number of notochordal cells (NCs). Whether the native NP matrix supports the homeostasis of notochordal cells is poorly understood. We hypothesized the NP matrix alone may contain sufficient regulatory factors and can serve as stimuli to generate notochordal cells (NCs) from human pluripotent stem cells. NCs are a promising cell sources for cell-based therapy to treat some types of intervertebral disc (IVD) degeneration. One major limitation of this emerging technique is the lack of available NCs as a potential therapeutic cell source. Human pluripotent stem cells derived from reprogramming or somatic cell nuclear transfer technique may yield stable and unlimited source for therapeutic use. We devised a new method to use porcine NP matrix to direct notochordal differentiation of human induced pluripotent stem cells (hiPSCs). The results showed that hiPSCs successfully differentiated into NC-like cells under the influence of devitalized porcine NP matrix. The NC-like cells expressed typical notochordal marker genes including brachyury (T), cytokeratin-8 (CK-8) and cytokeratin-18 (CK-18), and they displayed the ability to generate NP-like tissue in vitro, which was rich in aggrecan and collagen type II. These findings demonstrated the proof of concept for using native NP matrix to direct notochordal differentiation of hiPSCs. It provides a foundation for further understanding the biology of NCs, and eventually towards regenerative therapies for disc degeneration., (© 2014 Wiley Periodicals, Inc.)

The development of a new generation of injectable bone cements that are bioactive and have enhanced osteogenic capacity for rapid osseointegration is receiving considerable interest. In this study, a novel injectable cement (designated Sr-BBG) composed of strontium-doped borate bioactive glass particles and a chitosan-based bonding phase was prepared and evaluated in vitro and in vivo. The bioactive glass provided the benefits of bioactivity, conversion to hydroxyapatite, and the ability to stimulate osteogenesis, while the chitosan provided a cohesive biocompatible and biodegradable bonding phase. The Sr-BBG cement showed the ability to set in situ (initial setting time = 11.6 ± 1.2 min) and a compressive strength of 19 ± 1 MPa. The Sr-BBG cement enhanced the proliferation and osteogenic differentiation of human bone marrow-derived mesenchymal stem cells in vitro when compared to a similar cement (BBG) composed of chitosan-bonded borate bioactive glass particles without Sr. Microcomputed tomography and histology of critical-sized rabbit femoral condyle defects implanted with the cements showed the osteogenic capacity of the Sr-BBG cement. New bone was observed at different distances from the Sr-BBG implants within eight weeks. The bone-implant contact index was significantly higher for the Sr-BBG implant than it was for the BBG implant. Together, the results indicate that this Sr-BBG cement is a promising implant for healing irregularly shaped bone defects using minimally invasive surgery.

There is a need for better wound dressings that possess the requisite angiogenic capacity for rapid in situ healing of full-thickness skin wounds. Borate bioactive glass microfibers are showing a remarkable ability to heal soft tissue wounds but little is known about the process and mechanisms of healing. In the present study, wound dressings composed of borate bioactive glass microfibers (diameter = 0.4-1.2 μm; composition 6Na2O, 8K2O, 8MgO, 22CaO, 54B2O3, 2P2O5; mol%) doped with 0-3.0 wt.% CuO were created and evaluated in vitro and in vivo. When immersed in simulated body fluid, the fibers degraded and converted to hydroxyapatite within ∼7 days, releasing ions such as Ca, B and Cu into the medium. In vitro cell culture showed that the ionic dissolution product of the fibers was not toxic to human umbilical vein endothelial cells (HUVECs) and fibroblasts, promoted HUVEC migration, tubule formation and secretion of vascular endothelial growth factor (VEGF), and stimulated the expression of angiogenic-related genes of the fibroblasts. When used to treat full-thickness skin defects in rodents, the Cu-doped fibers (3.0 wt.% CuO) showed a significantly better capacity to stimulate angiogenesis than the undoped fibers and the untreated defects (control) at 7 and 14 days post-surgery. The defects treated with the Cu-doped and undoped fibers showed improved collagen deposition, maturity and orientation when compared to the untreated defects, the improvement shown by the Cu-doped fibers was not markedly better than the undoped fibers at 14 days post-surgery. These results indicate that the Cu-doped borate glass microfibers have a promising capacity to stimulate angiogenesis and heal full-thickness skin defects. They also provide valuable data for understanding the role of the microfibers in healing soft tissue wounds., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Biocompatible synthetic scaffolds with enhanced osteogenic and angiogenic capacity are of great interest for the repair of large (critical size) bone defects. In this study, we investigated an approach based on the controlled delivery of copper (Cu) ions from borate bioactive glass scaffolds for stimulating angiogenesis and osteogenesis in a rodent calvarial defect model. Borate glass scaffolds (pore size = 200-400 μm) doped with varying amounts of Cu (0-3.0 wt% CuO) were created using a polymer foam replication technique. When immersed in simulated body fluid (SBF) in vitro, the scaffolds released Cu ions into the medium at a rate that was dependent on the amount of Cu in the glass and simultaneously converted to hydroxyapatite (HA). At the concentrations used, the Cu in the glass was not cytotoxic to human bone marrow derived stem cells (hBMSCs) cultured on the scaffolds and the alkaline phosphatase activity of the hBMSCs increased with increasing Cu in the glass. When implanted in rat calvarial defects for 8 weeks, the scaffolds doped with 3 wt% CuO showed a significantly better capacity to stimulate angiogenesis and regenerate bone when compared to the undoped glass scaffolds. Together, these results indicate that the controlled delivery of Cu ions from borate bioactive glass implants is a promising approach in healing bone defects.

The repair of structural bone defects such as segmental defects in the long bones of the limbs is a challenging clinical problem. In this study, the capacity of silicate (13-93) and borate (13-93B3) bioactive glass scaffolds (porosity=47-50%) to heal critical-size segmental defects in rat femurs was evaluated and compared with autografts. Defects were implanted with 13-93 and 13-93B3 scaffolds with a grid-like microstructure (compressive strength=86 MPa and 40 MPa, respectively), 13-93B3 scaffolds with an oriented microstructure (compressive strength=32 MPa) and autografts using intramedullary fixation. Twelve weeks post-implantation, the defects were harvested and evaluated using histomorphometric analysis. The percentage of new bone in the defects implanted with the three groups of glass scaffolds (25-28%) and the total von Kossa-positive area (32-38%) were not significantly different from the autografts (new bone=38%; von Kossa-positive area=40%) (p>0.05). New blood vessel area in the defects implanted with the glass scaffolds (4-8%) and the autografts (5%) showed no significant difference among the four groups. New cartilage formed in the 13-93 grid-like scaffolds (18%) was significantly higher than in 13-93B3 grid-like scaffolds (8%) and in the autografts (8%) (p=0.02). The results indicate that these strong porous bioactive glass scaffolds are promising synthetic implants for structural bone repair., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Bacterial contamination of implanted orthopedic prostheses is a serious complication that requires prolonged systemic antibiotic therapy, major surgery to remove infected implants, bone reconstruction, and considerable morbidity. Local delivery of high doses of antibiotics using poly(methyl methacrylate) (PMMA) cement as the carrier, along with systemic antibiotics, is the standard treatment. However, PMMA is not biodegradable, and it can present a surface on which secondary bacterial infection can occur. PMMA spacers used to treat deep implant infections must be removed after resolution of the infection. Alternative carrier materials for antibiotics that could also restore deficient bone are therefore of interest. In this article, the development of bioactive glass-based materials as a delivery system for antibiotics is reviewed. Bioactive glass is osteoconductive, converts to hydroxyapatite, and heals to hard and soft tissues in vivo. Consequently, bioactive glass-based carriers can provide the combined functions of controlled local antibiotic delivery and bone restoration. Recently-developed borate bioactive glasses are of particular interest since they have controllable degradation rates coupled with desirable properties related to osteogenesis and angiogenesis. Such glasses have the potential for providing a new class of biomaterials, as substitutes for PMMA, in the treatment of deep bone infections., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Human induced pluripotent stem cells (hiPSCs) can differentiate into notochordal cell (NC)-like cells when cultured in the presence of natural porcine nucleus pulposus (NP) tissue matrix. The method promises massive production of high-quality, functional cells to treat degenerative intervertebral discs (IVDs). Based on our previous work, we further examined the effect of cell-NP matrix contact and culture medium on the differentiation, and further assessed the functional differentiation ability of the generated NC-like. The study showed that direct contact between hiPSCs and NP matrix can promote the differentiation yield, whilst both the contact and non-contact cultures can generate functional NC-like cells. The generated NC-like cells are highly homogenous regarding the expression of notochordal marker genes. A culture medium containing a cocktail of growth factors (FGF, EGF, VEGF and IGF-1) also supported the notochordal differentiation in the presence of NP matrix. The NC-like cells showed excellent functional differentiation ability to generate NP-like tissue which was rich in aggrecan and collagen type II; and particularly, the proteoglycan to collagen content ratio was as high as 12.5-17.5 which represents a phenotype close to NP rather than hyaline cartilage. Collectively, the present study confirmed the effectiveness and flexibility of using natural NP tissue matrix to direct notochordal differentiation of hiPSCs, and the potential of using the generated NC-like cells for treating IVD degeneration.

Three-dimensional porous scaffolds of a borosilicate bioactive glass (designated 13-93B1), with the composition 6Na2O-8K2O-8MgO-22CaO-18B2O3-36SiO2-2P2O5 (mol%), were prepared using a foam replication technique and evaluated in vitro and in vivo. Immersion of the scaffolds for 30 days in a simulated body fluid in vitro resulted in partial conversion of the glass to a porous hydroxyapatite composed of fine needle-like particles. The capacity of the scaffolds to support bone formation in vivo was evaluated in non-critical sized defects created in the femoral head of rabbits. Eight weeks post-implantation, the scaffolds were partially converted to hydroxyapatite, and they were well integrated with newly-formed bone. When loaded with platelet-rich plasma (PRP), the scaffolds supported bone regeneration in segmental defects in the diaphysis of rabbit radii. The results indicate that these 13-93B1 scaffolds, loaded with PRP or without PRP, are beneficial for bone repair due to their biocompatibility, conversion to hydroxyapatite, and in vivo bone regenerative properties., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Osteomyelitis (bone infection) is often difficult to cure. The commonly-used treatment of surgical debridement to remove the infected bone combined with prolonged systemic and local antibiotic treatment has limitations. In the present study, an injectable borate bioactive glass cement was developed as a carrier for the antibiotic vancomycin, characterized in vitro, and evaluated for its capacity to cure osteomyelitis in a rabbit tibial model. The cement (initial setting time = 5.8 ± 0.6 min; compressive strength = 25.6 ± 0.3 MPa) released vancomycin over ~25 days in phosphate-buffered saline, during which time the borate glass converted to hydroxyapatite (HA). When implanted in rabbit tibial defects infected with methicillin-resistant Staphylococcus aureus (MRSA)-induced osteomyelitis, the vancomycin-loaded cement converted to HA and supported new bone formation in the defects within 8 weeks. Osteomyelitis was cured in 87 % of the defects implanted with the vancomycin-loaded borate glass cement, compared to 71 % for the defects implanted with vancomycin-loaded calcium sulfate cement. The injectable borate bioactive glass cement developed in this study is a promising treatment for curing osteomyelitis and for regenerating bone in the defects following cure of the infection.

Background: A novel injectable cement composed of chitosan-bonded borate bioactive glass (BG) particles was evaluated as a carrier for local delivery of vancomycin in the treatment of osteomyelitis in a rabbit tibial model., Materials and Methods: The setting time, injectability, and compressive strength of the borate BG cement, and the release profile of vancomycin from the cement were measured in vitro. The capacity of the vancomycin-loaded BG cement to eradicate methicillin-resistant Staphylococcus aureus (MRSA)-induced osteomyelitis in rabbit tibiae in vivo was evaluated and compared with that for a vancomycin-loaded calcium sulfate (CS) cement and for intravenous injection of vancomycin., Results: The BG cement had an injectability of >90% during the first 3 minutes after mixing, hardened within 30 minutes and, after hardening, had a compressive strength of 18 ± 2 MPa. Vancomycin was released from the BG cement into phosphate-buffered saline for up to 36 days, and the cumulative amount of vancomycin released was 86% of the amount initially loaded into the cement. In comparison, vancomycin was released from the CS cement for up 28 days and the cumulative amount released was 89%. Two months post-surgery, radiography and microbiological tests showed that the BG and CS cements had a better ability to eradicate osteomyelitis when compared to intravenous injection of vancomycin, but there was no significant difference between the BG and CS cements in eradicating the infection. Histological examination showed that the BG cement was biocompatible and had a good capacity for regenerating bone in the tibial defects., Conclusions: These results indicate that borate BG cement is a promising material both as an injectable carrier for vancomycin in the eradication of osteomyelitis and as an osteoconductive matrix to regenerate bone after the infection is cured.

Borate bioactive glass has been shown to convert faster and more completely to hydroxyapatite and enhance new bone formation in vivo when compared to silicate bioactive glass (such as 45S5 and 13-93 bioactive glass). In this work, the effects of the borate glass microstructure on its conversion to hydroxyapatite (HA) in vitro and its ability to support tissue ingrowth in a rat subcutaneous implantation model were investigated. Bioactive borate glass scaffolds, designated 13-93B3, with a grid-like microstructure and pore widths of 300, 600, and 900 µm were prepared by a robocasting technique. The scaffolds were implanted subcutaneously for 4 weeks in Sprague Dawley rats. Silicate 13-93 glass scaffolds with the same microstructure were used as the control. The conversion of the scaffolds to HA was studied as a function of immersion time in a simulated body fluid. Histology and scanning electron microscopy were used to evaluate conversion of the bioactive glass implants to hydroxyapatite, as well as tissue ingrowth and blood vessel formation in the implants. The pore size of the scaffolds was found to have little effect on tissue infiltration and angiogenesis after the 4-week implantation.

The need for implants to repair large bone defects is driving the development of porous synthetic scaffolds with the requisite mechanical strength and toughness in vivo. Recent developments in the use of design principles and novel fabrication technologies are paving the way to create synthetic scaffolds with promising potential for reconstituting bone in load-bearing sites. This article reviews the state of the art in the design and fabrication of bioactive glass and ceramic scaffolds that have improved mechanical properties for structural bone repair. Scaffolds with anisotropic and periodic structures can be prepared with compressive strengths comparable to human cortical bone (100-150 MPa), while scaffolds with an isotropic structure typically have strengths in the range of trabecular bone (2-12 MPa). However, the mechanical response of bioactive glass and ceramic scaffolds in multiple loading modes such as flexure and torsion - as well as their mechanical reliability, fracture toughness, and fatigue resistance - has received little attention. Inspired by the designs of natural materials such as cortical bone and nacre, glass-ceramic and inorganic/polymer composite scaffolds created with extrinsic toughening mechanisms are showing potential for both high strength and mechanical reliability. Future research should include improved designs that provide strong scaffolds with microstructures conducive to bone ingrowth, and evaluation of these scaffolds in large animal models for eventual translation into clinical applications.

Previous studies have evaluated the capacity of porous scaffolds composed of a single bioactive glass to regenerate bone. In the present study, scaffolds composed of a mixture of two different bioactive glasses (silicate 13-93 and borate 13-93B3) were created and evaluated for their response to osteogenic MLO-A5 cells in vitro and their capacity to regenerate bone in rat calvarial defects in vivo. The scaffolds, which have similar microstructures (porosity=58-67%) and contain 0, 25, 50 and 100 wt.% 13-93B3 glass, were fabricated by thermally bonding randomly oriented short fibers. The silicate 13-93 scaffolds showed a better capacity to support cell proliferation and alkaline phosphatase activity than the scaffolds containing borate 13-93B3 fibers. The amount of new bone formed in the defects implanted with the 13-93 scaffolds at 12 weeks was 31%, compared to values of 25, 17 and 20%, respectively, for the scaffolds containing 25, 50 and 100% 13-93B3 glass. The amount of new bone formed in the 13-93 scaffolds was significantly higher than in the scaffolds containing 50 and 100% 13-93B3 glass. While the 13-93 fibers were only partially converted to hydroxyapatite at 12 weeks, the 13-93B3 fibers were fully converted and formed a tubular morphology. Scaffolds composed of an optimized mixture of silicate and borate bioactive glasses could provide the requisite architecture to guide bone regeneration combined with a controllable degradation rate that could be beneficial for bone and tissue healing., (Copyright © 2013 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Borate bioactive glass-based composites have been attracting interest recently as an osteoconductive carrier material for local antibiotic delivery. In the present study, composites composed of borate bioactive glass particles bonded with a chitosan matrix were prepared and evaluated in vitro as a carrier for gentamicin sulfate. The bioactivity, degradation, drug release profile, and compressive strength of the composite carrier system were studied as a function of immersion time in phosphate-buffered saline at 37 °C. The cytocompatibility of the gentamicin sulfate-loaded composite carrier was evaluated using assays of cell proliferation and alkaline phosphatase activity of osteogenic MC3T3-E1 cells. Sustained release of gentamicin sulfate occurred over ~28 days in PBS, while the bioactive glass converted continuously to hydroxyapatite. The compressive strength of the composite loaded with gentamicin sulfate decreased from the as-fabricated value of 24 ± 3 MPa to ~8 MPa after immersion for 14 days in PBS. Extracts of the soluble ionic products of the borate glass/chitosan composites enhanced the proliferation and alkaline phosphatase activity of MC3T3-E1 cells. These results indicate that the gentamicin sulfate-loaded composite composed of chitosan-bonded borate bioactive glass particles could be useful clinically as an osteoconductive carrier material for treating bone infection.

The regeneration of large bone defects is a common and significant clinical problem. Limitations associated with existing treatments such as autologous bone grafts and allografts have increased the need for synthetic bone graft substitutes. The objective of this study was to evaluate the capacity of novel hollow hydroxyapatite (HA) microspheres to serve as a carrier for controlled release of bone morphogenetic-2 (BMP2) in bone regeneration. Hollow HA microspheres (106-150 μm) with a high surface area (>100 m2 g(-1)) and a mesoporous shell wall (pore size 10-20 nm) were created using a glass conversion technique. The release of BMP2 from the microspheres into a medium composed of diluted fetal bovine serum in vitro was slow, but it occurred continuously for over 2 weeks. When implanted in rat calvarial defects for 3 or 6 weeks, the microspheres loaded with BMP2 (1 μg per defect) showed a significantly better capacity to regenerate bone than those without BMP2. The amount of new bone in the defects implanted with the BMP2-loaded microspheres was 40% and 43%, respectively, at 3 and 6 weeks, compared to 13% and 17%, respectively, for the microspheres without BMP2. Coating the BMP2-loaded microspheres with a biodegradable polymer, poly(lactic-co-glycolic acid), reduced the amount of BMP2 released in vitro and, above a certain coating thickness, significantly reduced bone regeneration in vivo. The results indicate that these hollow HA microspheres could provide a bioactive and osteoconductive carrier for growth factors in bone regeneration., (Copyright © 2013 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Borate bioactive glasses are biocompatible and enhance new bone formation, but the effect of their microstructure on bone regeneration has received little attention. In this study scaffolds of borate bioactive glass (1393B3) with three different microstructures (trabecular, fibrous, and oriented) were compared for their capacity to regenerate bone in a rat calvarial defect model. 12weeks post-implantation the amount of new bone, mineralization, and blood vessel area in the scaffolds were evaluated using histomorphometric analysis and scanning electron microscopy. The amount of new bone formed was 33%, 23%, and 15%, respectively, of the total defect area for the trabecular, oriented, and fibrous microstructures. In comparison, the percent new bone formed in implants composed of silicate 45S5 bioactive glass particles (250-300μm) was 19%. Doping the borate glass with copper (0.4 wt.% CuO) had little effect on bone regeneration in the trabecular and oriented scaffolds, but significantly enhanced bone regeneration in the fibrous scaffolds (from 15 to 33%). The scaffolds were completely converted to hydroxyapatite within the 12week implantation. The amount of hydroxyapatite formed, 22%, 35%, and 48%, respectively, for the trabecular, oriented, and fibrous scaffolds, increased with increasing volume fraction of glass in the as-fabricated scaffold. Blood vessels infiltrated into all the scaffolds, but the trabecular scaffolds had a higher average blood vessel area compared with the oriented and fibrous scaffolds. While all three scaffold microstructures were effective in supporting bone regeneration, the trabecular scaffolds supported more bone formation and may be more promising in bone repair., (Copyright © 2013 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

The development of inorganic-organic hybrid scaffolds with controllable degradation and bioactive properties is receiving considerable interest for bone and tissue regeneration. The objective of this study was to create hybrid scaffolds of gelatin and bioactive glass (BG) with a controlled, three-dimensional (3D) architecture by a combined sol-gel and robotic deposition (robocasting) method and evaluate their mechanical response, bioactivity, and response to cells in vitro. Inks for robotic deposition of the scaffolds were prepared by dissolving gelatin in a sol-gel precursor solution of the bioactive glass (70SiO2 -25CaO-5P2 O5 ; mol%) and aging the solution to form a gel with the requisite viscosity. After drying and crosslinking, the gelatin-BG scaffolds, with a grid-like architecture (filament diameter ∼350 µm; pore width ∼550 µm), showed an elasto-plastic response, with a compressive strength of 5.1 ± 0.6 MPa, in the range of values for human trabecular bone (2-12 MPa). When immersed in phosphate-buffered saline, the crosslinked scaffolds rapidly absorbed water (∼440% of its dry weight after 2 h) and showed an elastic response at deformations up to ∼60%. Immersion of the scaffolds in a simulated body fluid resulted in the formation of a hydroxyapatite-like surface layer within 5 days, indicating their bioactivity in vitro. The scaffolds supported the proliferation, alkaline phosphatase activity, and mineralization of osteogenic MC3T3-E1 cells in vitro, showing their biocompatibility. Altogether, the results indicate that these gelatin-BG hybrid scaffolds with a controlled, 3D architecture of inter-connected pores have potential for use as implants for bone regeneration., (Copyright © 2012 Wiley Periodicals, Inc.)

The repair of large bone defects, such as segmental defects in the long bones of the limbs, is a challenging clinical problem. Our recent work has shown the ability to create porous scaffolds of silicate 13-93 bioactive glass by robocasting which have compressive strengths comparable to human cortical bone. The objective of this study was to evaluate the capacity of those strong porous scaffolds with a grid-like microstructure (porosity=50%; filament width=330μm; pore width=300μm) to regenerate bone in a rat calvarial defect model. Six weeks post-implantation, the amount of new bone formed within the implants was evaluated using histomorphometric analysis. The amount of new bone formed in implants composed of the as-fabricated scaffolds was 32% of the available pore space (area). Pretreating the as-fabricated scaffolds in an aqueous phosphate solution for 1, 3 and 6days to convert a surface layer to hydroxyapatite prior to implantation enhanced new bone formation to 46%, 57% and 45%, respectively. New bone formation in scaffolds pretreated for 1, 3 and 6days and loaded with bone morphogenetic protein-2 (BMP-2) (1μg per defect) was 65%, 61% and 64%, respectively. The results show that converting a surface layer of the glass to hydroxyapatite or loading the surface-treated scaffolds with BMP-2 can significantly improve the capacity of 13-93 bioactive glass scaffolds to regenerate bone in an osseous defect. Based on their mechanical properties evaluated previously and their capacity to regenerate bone found in this study, these 13-93 bioactive glass scaffolds, pretreated or loaded with BMP-2, are promising in structural bone repair., (Copyright © 2013 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

There is a need to develop synthetic scaffolds to repair large defects in load-bearing bones. Bioactive glasses have attractive properties as a scaffold material for bone repair, but data on their mechanical properties are limited. The objective of the present study was to comprehensively evaluate the mechanical properties of strong porous scaffolds of silicate 13-93 bioactive glass fabricated by robocasting. As-fabricated scaffolds with a grid-like microstructure (porosity 47%, filament diameter 330μm, pore width 300μm) were tested in compressive and flexural loading to determine their strength, elastic modulus, Weibull modulus, fatigue resistance, and fracture toughness. Scaffolds were also tested in compression after they were immersed in simulated body fluid (SBF) in vitro or implanted in a rat subcutaneous model in vivo. As fabricated, the scaffolds had a strength of 86±9MPa, elastic modulus of 13±2GPa, and a Weibull modulus of 12 when tested in compression. In flexural loading the strength, elastic modulus, and Weibull modulus were 11±3MPa, 13±2GPa, and 6, respectively. In compression, the as-fabricated scaffolds had a mean fatigue life of ∼10(6) cycles when tested in air at room temperature or in phosphate-buffered saline at 37°C under cyclic stresses of 1-10 or 2-20MPa. The compressive strength of the scaffolds decreased markedly during the first 2weeks of immersion in SBF or implantation in vivo, but more slowly thereafter. The brittle mechanical response of the scaffolds in vitro changed to an elasto-plastic response after implantation for longer than 2-4weeks in vivo. In addition to providing critically needed data for designing bioactive glass scaffolds, the results are promising for the application of these strong porous scaffolds in loaded bone repair., (Copyright © 2013 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Implants that simultaneously function as an osteoconductive matrix and as a device for local drug or growth factor delivery could provide an attractive system for bone regeneration. In our previous work, we prepared hollow hydroxyapatite (abbreviated HA) microspheres with a high surface area and mesoporous shell wall and studied the release of a model protein, bovine serum albumin (BSA), from the microspheres into phosphate-buffered saline (PBS). The present work is an extension of our previous work to study the release of BSA from similar HA microspheres into a biocompatible hydrogel, poly(ethylene glycol) (PEG). BSA-loaded HA microspheres were placed in a PEG solution which was rapidly gelled using ultraviolet radiation. The BSA release rate into the PEG hydrogel, measured using a spectrophotometric method, was slower than into PBS, and it was dependent on the initial BSA loading and on the microstructure of the microsphere shell wall. A total of 35-40% of the BSA initially loaded into the microspheres was released into PEG over ~14 days. The results indicate that these hollow HA microspheres have promising potential as an osteoconductive device for local drug or growth factor delivery in bone regeneration and in the treatment of bone diseases., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Implants that serve simultaneously as an osteoconductive matrix and as a device for local growth factor delivery may be required for optimal bone regeneration in some applications. In the present study, hollow hydroxyapatite (HA) microspheres (106-150μm) in the form of three-dimensional (3-D) scaffolds or individual (loose) microspheres were created using a glass conversion process. The capacity of the implants, with or without transforming growth factor β1 (TGF-β1), to regenerate bone in a rat calvarial defect model was compared. The 3-D scaffolds supported the proliferation and alkaline phosphatase activity of osteogenic MLO-A5 cells in vitro, showing their cytocompatibility. Release of TGF-β1 from the 3-D scaffolds into phosphate-buffered saline ceased after 2-3 days when ∼30% of the growth factor was released. Bone regeneration in the 3-D scaffolds and the individual microspheres increased with time from 6 to 12 weeks, but it was significantly higher (23%) in the individual microspheres than in the 3-D scaffolds (15%) after 12 weeks. Loading with TGF-β1 (5μg per defect) enhanced bone regeneration in the 3-D scaffolds and individual microspheres after 6 weeks, but had little effect after 12 weeks. 3-D scaffolds and individual microspheres with larger HA diameter (150-250μm) showed better ability to regenerate bone. Based on these results, implants composed of hollow HA microspheres show promising potential as an osteoconductive matrix for local growth factor delivery in bone regeneration., (Copyright © 2012 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Microfibrous bioactive glasses are showing a considerable capacity to heal soft tissue wounds, but little information is available on the mechanism of healing. In the present study, the conversion of microfibrous borate bioactive glass (diameter = 0.2-5 μm) with the composition designated 13-93B3 (5.5 Na2O, 11.1 K2O, 4.6 MgO, 18.5 CaO, 3.7 P2O5, 56.6 B2O3 wt%) was evaluated in vitro as a function of immersion time in a simulated body fluid (SBF) at 37 °C using structural and chemical techniques. Silicate 45S5glass microfibers (45 SiO2, 24.5 Na2O, 24.5 CaO, 6 P2O5 wt%) were also studied for comparison. Microfibrous 13-93B3 glass degraded almost completely and converted to a calcium phosphate material within 7-14 days in SBF, whereas >85 % of the silica remained in the 45S5 microfibers, forming a silica gel phase. An amorphous calcium phosphate (ACP) product that formed on the 13-93B3 microfibers crystallized at a slower rate to hydroxyapatite (HA) when compared to the ACP that formed on the 45S5 fibers. For immersion times >3 days, the 13-93B3 fibers released a higher concentration of Ca into the SBF than the 45S5 fibers. The fast and more complete degradation, slow crystallization of the ACP product, and higher concentration of dissolved Ca in SBF could contribute to the capacity of the microfibrous borate 13-93B3 glass to heal soft tissue wounds.

There is a need for synthetic bone graft substitutes to repair large bone defects resulting from trauma, malignancy and congenital diseases. Bioactive glass has attractive properties as a scaffold material but factors that influence its ability to regenerate bone in vivo are not well understood. In the present work, the ability of strong porous scaffolds of 13-93 bioactive glass with an oriented microstructure to regenerate bone was evaluated in vivo using a rat calvarial defect model. Scaffolds with an oriented microstructure of columnar pores (porosity=50%; pore diameter=50-150 μm) showed mostly osteoconductive bone regeneration, and new bone formation, normalized to the available pore area (volume) of the scaffolds, increased from 37% at 12 weeks to 55% at 24 weeks. Scaffolds of the same glass with a trabecular microstructure (porosity=80%; pore width=100-500 μm), used as the positive control, showed bone regeneration in the pores of 25% and 46% at 12 and 24 weeks, respectively. The brittle mechanical response of the as-fabricated scaffolds changed markedly to an elastoplastic response in vivo at both implantation times. These results indicate that both groups of 13-93 bioactive glass scaffolds could potentially be used to repair large bone defects, but scaffolds with the oriented microstructure could also be considered for the repair of loaded bone., (Copyright © 2012 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Silicon nitride (Si(3)N(4)) is an industrial ceramic used in spinal fusion and maxillofacial reconstruction. Maximizing bone formation and minimizing bacterial infection are desirable attributes in orthopedic implants designed to adhere to living bone. This study has compared these attributes of Si(3)N(4) implants with implants made from two other orthopedic biomaterials, i.e. poly(ether ether ketone) (PEEK) and titanium (Ti). Dense implants made of Si(3)N(4), PEEK, or Ti were surgically implanted into matching rat calvarial defects. Bacterial infection was induced with an injection of 1×10(4)Staphylococcus epidermidis. Control animals received saline only. On 3, 7, and 14days, and 3months post-surgery four rats per time period and material were killed, and calvariae were examined to quantify new bone formation and the presence or absence of bacteria. Quantitative evaluation of osteointegration to adjacent bone was done by measuring the resistance to implant push-out (n=8 rats each for Ti and PEEK, and n=16 rats for Si(3)N(4)). Three months after surgery in the absence of bacterial injection new bone formation around Si(3)N(4) was ∼69%, compared with 24% and 36% for PEEK and Ti, respectively. In the presence of bacteria new bone formation for Si(3)N(4), Ti, and PEEK was 41%, 26%, and 21%, respectively. Live bacteria were identified around PEEK (88%) and Ti (21%) implants, whereas none were present adjacent to Si(3)N(4). Push-out strength testing demonstrated statistically superior bone growth onto Si(3)N(4) compared with Ti and PEEK. Si(3)N(4) bioceramic implants demonstrated superior new bone formation and resistance to bacterial infection compared with Ti and PEEK., (Copyright © 2012 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

This in vitro study was performed to evaluate the ability of two types of porous bioactive glass scaffolds to support the growth and differentiation of an established osteogenic cell line. The two scaffold types tested included 13-93 glass fiber and trabecular-like scaffolds seeded with murine MLO-A5 cells and cultured for intervals of 2 to 12 days. Culture in MTT-containing medium showed metabolically active cells both on the surface and within the interior of the scaffolds. Scanning electron microscopy revealed well-attached cells on both types of scaffolds with a continual increase in cell density over a 6-day period. Protein measurements also showed a linear increase in cell density during the incubation. Activity of alkaline phosphatase, a key indicator of osteoblast differentiation, increased about 10-fold during the 6-day incubation with both scaffold types. The addition of mineralization media to MLO-A5 seeded scaffolds triggered extensive formation of alizarin red-positive mineralized extracellular material, additional evidence of cell differentiation and completion of the final step of bone formation on the constructs. Collectively, the results indicate that the 13-93 glass fiber and trabecular scaffolds promote the attachment, growth, and differentiation of MLO-A5 osteogenic cells and could potentially be used for bone tissue engineering applications., (Copyright © 2012 Wiley Periodicals, Inc.)

Silicon nitride (Si(3)N(4)) is a ceramic material developed for industrial applications that demand high strength and fracture resistance under extreme operating conditions. Recently, Si(3)N(4) has been used as an orthopedic biomaterial, to promote bone fusion in spinal surgery and to develop bearings that can improve the wear and longevity of prosthetic hip and knee joints. Si(3)N(4) has been implanted in human patients for over 3 years now, and clinical trials with Si(3)N(4) femoral heads in prosthetic hip replacement are contemplated. This review will provide background information and data relating to Si(3)N(4) ceramics that will be of interest to engineering and medical professionals., (Copyright © 2012 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

An important objective in bone tissue engineering is to fabricate biomimetic three-dimensional scaffolds that stimulate mineralization for rapid regeneration of bone. In this work, scaffolds of electrospun poly(vinyl alcohol) (PVA) fibers (diameter = 286 ± 14 nm) were coated with a sol-gel derived bioactive glass (BG) and evaluated in vitro for potential applications in bone repair. Structural and chemical analyses showed that the BG coating was homogeneously deposited on the PVA fibers. In vitro cell culture studies showed that the BG-coated PVA scaffold had a greater capacity to support proliferation of osteogenic MC3T3-E1 cells, alkaline phosphatase activity, and mineralization than the uncoated PVA scaffold. The BG coating improved the tensile strength of the PVA scaffold from 18 ± 2 MPa to 21 ± 2 MPa, but reduced the elongation to failure from 94 ± 4% to 64 ± 5%. However, immersion of the BG-coated PVA scaffolds in a simulated body fluid for 5 days resulted in an increase in the tensile strength (24 ± 2 MPa) and elongation to failure (159 ± 4%). Together, the results show that these BG-coated PVA scaffolds could be considered as candidate materials for bone tissue engineering applications., (Copyright © 2012 Wiley Periodicals, Inc.)

The conversion of 45S5 glass and glass-ceramics to a hydroxyapatite (HA)-like material in vitro has been studied extensively, but only for short reaction times (typically <3 months). In this paper, we report for the first time on the long-term conversion of 45S5 glass-ceramic microspheres (designated 45S5c) in an aqueous phosphate solution. Microspheres of 45S5c (75-150 μm) were immersed for 10 years at room temperature (~25 °C) in K(2)HPO(4) solution with a concentration of 0.01 M or 1.0 M, and with a starting pH of 7.0 or 9.5. The reacted 45S5c microspheres and solutions were analyzed using structural and analytical techniques. Only 25-45 vol% of the 45S5c microspheres were converted to an HA-like material after the 10 year reaction. In solutions with a starting pH of 9.5, an increase in the K(2)HPO(4) concentration from 0.01 to 1.0 M resulted in a doubling of the volume of the microspheres converted to an HA-like material but had little effect on the composition of the HA-like product. In comparison, reaction of the 45S5c microspheres in the solution with a starting pH of 7.0 resulted in an HA-like product in the 0.01 M K(2)HPO(4) solution but a calcium pyrophosphate product, Ca(10)K(4)(P(2)O(7))(6).9H(2)O, in the 1.0 M solution. The consequences of these results for the long-term use of 45S5 glass-ceramics in biomedical applications are discussed.

Scaffolds of 13-93 bioactive glass (6Na(2)O, 12K(2)O, 5MgO, 20CaO, 4P(2)O(5), 53SiO(2); wt.%) with an oriented pore architecture were formed by unidirectional freezing of camphene-based suspensions, followed by thermal annealing of the frozen constructs to grow the camphene crystals. After sublimation of the camphene, the constructs were sintered (1 h at 700°C) to produce a dense glass phase with oriented macropores. The objective of this work was to study how constant freezing rates (1-7°C min(-1)) during the freezing step influenced the pore orientation and mechanical response of the scaffolds. When compared to scaffolds prepared by freezing the suspensions on a substrate kept at a constant temperature of 3°C (time-dependent freezing rate), higher freezing rates resulted in better pore orientation, a more homogeneous microstructure and a marked improvement in the mechanical response of the scaffolds in compression. Scaffolds fabricated using a constant freezing rate of 7°C min(-1) (porosity=50±4%; average pore diameter=100 μm), had a compressive strength of 47±5 MPa and an elastic modulus of 11±3 GPa (in the orientation direction). In comparison, scaffolds prepared by freezing on the constant-temperature substrate had strength and modulus values of 35±11 MPa and 8±3 GPa, respectively. These oriented bioactive glass scaffolds prepared by the constant freezing rate route could potentially be used for the repair of defects in load-bearing bones, such as segmental defects in the long bones., (Copyright © 2011 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)