Manufacturing and Characterization of Dental Crowns Made of 5-mol% Yttria Stabilized Zirconia by Digital Light Processing.

We herein report manufacturing of dental crowns made of 5-mol% yttria partially stabilized zirconia (5Y-PSZ) with desired mechanical properties, optical translucency and dimensional accuracy using digital light processing (DLP). To this end, all processing parameters were carefully controlled and optimized. First, 5Y-PSZ particles with a bimodal distribution were prepared via calcination of as-received granules and subsequent ball-milling and then used to formulate 5Y-PSZ suspensions with a high solid loading of 50 vol% required for high densification after sintering. Dispersant content was also optimized. To provide high dimensional accuracy, initial dimensions of dental crowns for 3D printing were precisely determined by considering increase and decrease in dimensions during photopolymerization and sintering, respectively. Photopolymerization time was also optimized for a given layer thickness of 50 µm to ensure good bonding between layers. A multi-step debinding schedule with a slow heating rate was employed to avoid formation of any defects. After sintering at 1500 °C for 2 h, 5Y-PSZ could be almost fully densified without noticeable defects within layers and at interfaces between layers. They had high relative densities (99.03 ± 0.39%) with a high cubic phase content (59.1%). These characteristics allowed for achievement of reasonably high mechanical properties (flexural strength = 625.4 ± 75.5 MPa and Weibull modulus = 7.9) and % transmittance (31.4 ± 0.7%). In addition, 5Y-PSZ dental crowns showed excellent dimensional accuracy (root mean square (RMS) for marginal discrepancy = 44.4 ± 10.8 µm and RMS for internal gap = 22.8 ± 1.6 µm) evaluated by the 3D scanning technique.

Digital Light Processing of Zirconia Suspensions Containing Photocurable Monomer/Camphor Vehicle for Dental Applications.

This study reports the utility of solid camphor as a novel diluent in photocurable hexanediol diacrylate (HDDA) monomer to manufacture 4 mol% yttria partially stabilized zirconia (4Y-PSZ) components for dental applications by digital light processing (DLP). The use of a 65 wt% HDDA-35 wt% camphor solution allowed 4Y-PSZ suspensions to have reasonably low viscosities (1399 ± 55.8 mPa·s at a shear rate of 75 s-1), measured by a cone/plate viscometer, at a high solid loading of 48 vol%, where 4Y-PSZ particles prepared by calcination of as-received 4Y-PSZ granules, followed by a ball-milling process, were used with assistance of a dispersant. These 4Y-PSZ suspensions could be successfully applied to our custom-made DLP machine for manufacturing 4Y-PSZ components. To this end, several processing parameters, including layer thickness of 4Y-PSZ suspension, UV illumination time for layer-by-layer photocuring process, and initial dimensions of 4Y-PSZ objects, were tightly controlled. As sintering temperature increased from 1300 °C to 1500 °C, relative density and grain size of 4Y-PSZ objects increased, and cubic phase content also increased. Thus, after sintering at the highest temperature of 1500 °C for 3 h, high mechanical properties (biaxial flexural strength = 911 ± 40.7 MPa, hardness = 1371 ± 14.4 Hv) and reasonably high optical transmittance (translucency parameter = 7.77 ± 0.32, contrast ratio = 0.809 ± 0.007), evaluated by a spectrophotometer, were obtained due to a high relative density (97.2 ± 1.38%), which would be useful for dental applications.

Dual-Scale Porosity Alumina Structures Using Ceramic/Camphene Suspensions Containing Polymer Microspheres.

This study demonstrates the utility of thermo-regulated phase separable alumina/camphene suspensions containing poly(methyl methacrylate) (PMMA) microspheres as porogens for the production of multi-scale porosity structures. The homogeneous suspension prepared at 60 °C could undergo phase separation during freezing at room temperature. This process resulted in the 3D networks of camphene crystals and alumina walls containing PMMA microspheres. As a consequence, relatively large dendritic pores with several tens of microns size could be created as the replica of frozen camphene crystals. In addition, after the removal of PMMA microspheres via heat-treatment, micron-sized small spherical pores could be generated in alumina walls. As the PMMA content with respect to the alumina content increased from 0 vol% to 40 vol%, while the camphene content in the suspensions was kept constant (70 vol%), the overall porosity increased from 45.7 ± 0.5 vol% to 71.4 ± 0.5 vol%. This increase in porosity is attributed to an increase in the fraction of spherical pores in the alumina walls. Thus, compressive strength decreased from 153 ± 18.3 MPa to 33 ± 7.2 MPa. In addition, multi-scale porosity alumina objects with a honeycomb structure comprising periodic hexagonal macrochannels surrounded by dual-scale porosity walls were constructed using a 3D plotting technique.

Enhanced Mechanical Strength, Flexibility, and Shape-Restoring Rate of a Drug-Eluting Shape-Memory Polymer by Incorporation of Supramolecular Cross-Linkers.

The purpose of this study is to develop mechanically robust soybean oil and polycaprolactone (PC)-based drug-eluting shape memory polymers (SMPs) containing polyrotaxane (PRX) cross-linkers. Essentially, the dynamic PRX cross-linker-containing methacrylate group is introduced to increase the cross-linking density and flexibility of the SMP to overcome its mechanical limitations. It was confirmed that the elongation and cross-linking density of the PRX-incorporated SMP were increased by 2-4 times compared to neat SMP. In addition, those high mechanical properties of the PRX-incorporated SMP could be maintained after the degradation of the PC by the drug-eluting process.

Digital Light Processing of Freeze-cast Ceramic Layers for Macroporous Calcium Phosphate Scaffolds with Tailored Microporous Frameworks.

The objective of the present study is to demonstrate the versatility of the digital light processing (DLP) technique particularly when using a freeze-cast ceramic layer as the feedstock, which can manufacture porous calcium phosphate (CaP) scaffolds with arbitrarily designed macroporous structures with tailored microporous frameworks specially designed for bone scaffold applications. For this goal, we employed camphene-camphor as the freezing vehicle and porogen for the preparation of photocurable CaP suspensions containing diurethane dimethacrylate (UDMA) monomers. After freeze-casting, the CaP suspensions could be solidified at controlled temperatures (~33-38 °C) and then be photopolymerized by DLP. All produced CaP scaffolds fairly resembled the designed macroporous structures (the gyroid structure with two interpenetrating macropore networks). In addition, numerous micropores were created in the CaP filaments, while the microporosity increased with increasing the camphene-camphor amount from 40 vol % to 60 vol %. As a consequence, compressive strength and modulus of hierarchically porous CaP scaffolds decreased due to an increase in overall porosity. However, reasonable mechanical properties could be obtained at high porosities owing to the CaP frameworks constructed in a periodic manner. In addition, excellent water penetration capability, biocompatibility, and apatite-forming ability were obtained, which were attributed to the microporous CaP frameworks with good pore interconnectivity and large surface area.

3D Plotting using Camphene as Pore-regulating Agent to Produce Hierarchical Macro/micro-porous Poly(ε-caprolactone)/calcium phosphate Composite Scaffolds.

This study demonstrates the utility of camphene as the pore-regulating agent for phase separation-based 3D plotting to produce hierarchical macro/micro-porous poly(ε-caprolactone) (PCL)-calcium phosphate (CaP) composite scaffolds, specifically featuring highly microporous surfaces. Unlike conventional particulate porogens, camphene is highly soluble in acetone, the solvent for PCL polymer, but insoluble in coagulation medium (water). In this study, this unique characteristic supported the creation of numerous micropores both within and at the surfaces of PCL and PCL-CaP composite filaments when using high camphene contents (40 and 50 wt%). In addition, the incorporation of the CaP particles into PCL solutions did not deteriorate the formation of microporous structures, and thus hierarchical macro/micro-porous PCL-CaP composite scaffolds could be successfully produced. As the CaP content increased, the in vitro biocompatibility, apatite-forming ability, and mechanical properties (tensile strength, tensile modulus, and compressive modulus) of the PCL-CaP composite scaffolds were substantially improved.

Biomimetic porous Mg with tunable mechanical properties and biodegradation rates for bone regeneration.

The medical applications of porous Mg scaffolds are limited owing to its rapid corrosion, which dramatically decreases the mechanical strength of the scaffold. Mimicking the bone structure and composition can improve the mechanical and biological properties of porous Mg scaffolds. The Mg structure can also be coated with HA by an aqueous precipitation coating method to enhance both the corrosion resistance and the biocompatibility. However, due to the brittleness of HA coating layer, cracks tend to form in the HA coating layer, which may influence the corrosion and biological functionality of the scaffold. Consequently, in this study, hybrid poly(ether imide) (PEI)-SiO2 layers were applied to the HA-coated biomimetic porous Mg to impart the structure with the high corrosion resistance associated with PEI and excellent bioactivity with SiO2. The porosity of the Mg was controlled by adjusting the concentration of the sodium chloride (NaCl) particles used in the fabrication via the space-holder method. The mechanical measurements showed that the compressive strength and stiffness of the biomimetic porous Mg increased as the portion of the dense region increased. In addition, following results show that HA/(PEI-SiO2) hybrid-coated biomimetic Mg is a promising biodegradable scaffold for orthopedic applications. In-vitro testing revealed that the proposed hybrid coating reduced the degradation rate and facilitated osteoblast spreading compared to HA- and HA/PEI-coating scaffolds. Moreover, in-vivo testing with a rabbit femoropatellar groove model showed improved tissue formation, reduced corrosion and degradation, and improved bone formation on the scaffold. STATEMENT OF SIGNIFICANCE: Porous Mg is a promising biodegradable scaffold for orthopedic applications. However, there are limitations in applying porous Mg for an orthopedic biomaterial due to its poor mechanical properties and susceptibility to rapid corrosion. Here, we strategically designed the structure and coating layer of porous Mg to overcome these limitations. First, porous Mg was fabricated by mimicking the bone structure which has a combined structure of dense and porous regions, thus resulting in an enhancement of mechanical properties. Furthermore, the biomimetic porous Mg was coated with HA/(PEI-SiO2) hybrid layer to improve both corrosion resistance and biocompatibility. As the final outcome, with tunable mechanical and biodegradable properties, HA/(PEI-SiO2)-coated biomimetic porous Mg could be a promising candidate material for load-bearing orthopedic applications.

Porous Calcium Phosphate Ceramic Scaffolds with Tailored Pore Orientations and Mechanical Properties Using Lithography-Based Ceramic 3D Printing Technique.

This study demonstrates the usefulness of the lithography-based ceramic 3-dimensional printing technique with a specifically designed top-down process for the production of porous calcium phosphate (CaP) ceramic scaffolds with tailored pore orientations and mechanical properties. The processing parameters including the preparation of a photocurable CaP slurry with a high solid loading (φ = 45 vol%), the exposure time for photocuring process, and the initial designs of the porous scaffolds were carefully controlled. Three types of porous CaP scaffolds with different pore orientations (i.e., 0°/90°, 0°/45°/90°/135°, and 0°/30°/60°/90°/120°/150°) were produced. All the scaffolds exhibited a tightly controlled porous structure with straight CaP frameworks arranged in a periodic pattern while the porosity was kept constant. The porous CaP scaffold with a pore orientation of 0°/90° demonstrated the highest compressive strength and modulus due to a number of CaP frameworks parallel to the loading direction. On the other hand, scaffolds with multiple pore orientations may exhibit more isotropic mechanical properties regardless of the loading directions. The porous CaP scaffolds exhibited an excellent in vitro apatite-forming ability in a stimulated body fluid (SBF) solution. These findings suggest that porous CaP scaffolds with tailored pore orientations may provide tunable mechanical properties with good bone regeneration ability.

Coextrusion-Based 3D Plotting of Ceramic Pastes for Porous Calcium Phosphate Scaffolds Comprised of Hollow Filaments.

This paper demonstrates the utility of coextrusion-based 3D plotting of ceramic pastes (CoEx-3DP) as a new type of additive manufacturing (AM) technique, which can produce porous calcium phosphate (CaP) ceramic scaffolds comprised of hollow CaP filaments. In this technique, green filaments with a controlled core/shell structure can be produced by coextruding an initial feedrod, comprised of the carbon black (CB) core and CaP shell, through a fine nozzle in an acetone bath and then deposited in a controlled manner according to predetermined paths. In addition, channels in CaP filaments can be created through the removal of the CB cores during heat-treatment. Produced CaP scaffolds had two different types of pores with well-defined geometries: three-dimensionally interconnected pores (~360 × 230 µm² in sizes) and channels (>100 µm in diameter) in hollow CaP filaments. The porous scaffolds showed high compressive strengths of ~12.3 ± 2.2 MPa at a high porosity of ~73 vol % when compressed parallel to the direction of the hollow CaP filaments. In addition, the mechanical properties of porous CaP scaffolds could be tailored by adjusting their porosity, for example, compressive strengths of 4.8 ± 1.1 MPa at a porosity of ~82 vol %. The porous CaP scaffold showed good biocompatibility, which was assessed by in vitro cell tests, where several the cells adhered to and spread actively with the outer and inner surfaces of the hollow CaP filaments.

Novel Self-Assembly-Induced Gelation for Nanofibrous Collagen/Hydroxyapatite Composite Microspheres.

This study demonstrates the utility of the newly developed self-assembly-induced gelation technique for the synthesis of porous collagen/hydroxyapatite (HA) composite microspheres with a nanofibrous structure. This new approach can produce microspheres of a uniform size using the droplets that form at the nozzle tip before gelation. These microspheres can have a highly nanofibrous structure due to the immersion of the droplets in a coagulation bath (water/acetone), in which the collagen aggregates in the solution can self-assemble into fibrils due to pH-dependent precipitation. Bioactive HA particles were incorporated into the collagen solutions, in order to enhance the bioactivity of the composite microspheres. The composite microspheres exhibited a well-defined spherical morphology and a uniform size for all levels of HA content (0 wt %, 10 wt %, 15 wt %, and 20 wt %). Collagen nanofibers-several tens of nanometers in size-were uniformly present throughout the microspheres and the HA particles were also well dispersed. The in vitro apatite-forming ability, assessed using the simulated body fluid (SBF) solution, increased significantly with the incorporation of HA into the composite microspheres.

Production of Poly(ε-Caprolactone)/Hydroxyapatite Composite Scaffolds with a Tailored Macro/Micro-Porous Structure, High Mechanical Properties, and Excellent Bioactivity.

We produced poro-us poly(ε-caprolactone) (PCL)/hydroxyapatite (HA) composite scaffolds for bone regeneration, which can have a tailored macro/micro-porous structure with high mechanical properties and excellent in vitro bioactivity using non-solvent-induced phase separation (NIPS)-based 3D plotting. This innovative 3D plotting technique can create highly microporous PCL/HA composite filaments by inducing unique phase separation in PCL/HA solutions through the non-solvent-solvent exchange phenomenon. The PCL/HA composite scaffolds produced with various HA contents (0 wt %, 10 wt %, 15 wt %, and 20 wt %) showed that PCL/HA composite struts with highly microporous structures were well constructed in a controlled periodic pattern. Similar levels of overall porosity (~78 vol %) and pore size (~248 µm) were observed for all the PCL/HA composite scaffolds, which would be highly beneficial to bone tissue regeneration. Mechanical properties, such as ultimate tensile strength and compressive yield strength, increased with an increase in HA content. In addition, incorporating bioactive HA particles into the PCL polymer led to remarkable enhancements in in vitro apatite-forming ability.

Design and Production of Continuously Gradient Macro/Microporous Calcium Phosphate (CaP) Scaffolds Using Ceramic/Camphene-Based 3D Extrusion.

This study proposes a new type of calcium phosphate (CaP) scaffolds with a continuously gradient macro/microporous structure using the ceramic/camphene-based 3D extrusion process. Green filaments with a continuously gradient core/shell structure were successfully produced by extruding a bilayered feedrod comprised of a CaP/camphene mixture lower part and a pure camphene upper part. The extruded filaments were then deposited in a controlled manner to construct triangular prisms, followed by the assembly process for the production of CaP scaffolds with a gradient core/shell structure. In addition, a gradient microporous structure was created by heat-treating the green body at 43 °C to induce the overgrowth of camphene dendrites in the CaP/camphene walls. The produced CaP scaffold showed a highly macroporous structure within its inner core, where the size of macrochannels increased gradually with an increase in the distance from the outer shell, while relatively larger micropores were created in the outer shell.

Cytocompatibility of Ti3AlC2, Ti3SiC2, and Ti2AlN: In Vitro Tests and First-Principles Calculations.

Herein, the cytocompatibility of selected MAX phases, Ti3AlC2, Ti3SiC2, and Ti2AlN, were systematically evaluated using in vitro tests for the first time. These phases were anoxic to preosteoblasts and fibroblasts. Compared with the strong viable fibroblasts, the different cellular responses of these materials were clearly distinguishable for the preosteoblasts. Under an osteoblastic environment, Ti2AlN exhibited better cell proliferation and differentiation performance than Ti3AlC2 and Ti3SiC2. Moreover, the performance was superior to that of a commercial Ti-6Al-4V alloy and comparable to that of pure Ti. A possible mechanism was suggested based on the different surface oxidation products, which were determined from the binding energy of adsorbed Ca2+ ions using first-principles calculations. Compared with the partially oxidized TiCxOy layer on Ti3AlC2 and Ti3SiC2, the partially oxidized TiNxOy layer on the Ti2AlN had a stronger affinity to the Ca2+ ions, which indicated the good cytocompatibility of Ti2AlN.

Poly(ether imide)-silica hybrid coatings for tunable corrosion behavior and improved biocompatibility of magnesium implants.

Magnesium (Mg) and its alloys have gained considerable attention as a promising biomaterial for bioresorbable orthopedic implants, but the corrosion behavior of Mg-based implants is still the major issue for clinical use. In order to improve the corrosion stability and implant-tissue interfaces of these implants, methods for coating Mg have been actively investigated. In this study, poly(ether imide) (PEI)-silica hybrid material was coated on Mg, for the tunable degradation and enhanced biological behavior. Homogeneous PEI-silica hybrid materials with various silica contents were coated on Mg substrates without any cracks, where silica nanoparticles were well dispersed in the PEI matrix without significant particle agglomeration up the 30 vol% silica. The hybrid coatings maintained good adhesion strength of PEI to Mg. The corrosion rate of hybrid-coated Mg was increased along with the increment of the silica content, due to improved hydrophilicity of the hybrid coating layers. Moreover, the biocompatibility of the hybrid-coated Mg specimens was significantly improved, mainly due to the higher Mg ion concentrations associated with faster corrosion, compared to PEI-coated Mg. Therefore, PEI-silica hybrid systems have significant potential as a coating material of Mg for load-bearing orthopedic applications by providing tunable corrosion behavior and enhanced biological performance.

Synthesis of nanofibrous gelatin/silica bioglass composite microspheres using emulsion coupled with thermally induced phase separation.

This study proposes an innovative way of synthesizing porous gelatin/silica bioglass composite microspheres with a nanofibrous structure using emulsion coupled with thermally induced phase separation (TIPS). In particular, a mixture of the solvent (water) and non-solvent (ethanol) was used to induce a unique phase separation of gelatin/silica mixtures (i.e. gelatin/silica hybrid-rich and liquid-rich phases) at -70 °C for the creation of a nanofibrous structure. All the composite microspheres synthesized with silica contents of 10 wt.%, 15 wt.%, and 20 wt.% had well-defined spherical shapes between 124 and 136 µm in size. In addition, they were comprised of nanofibrous gelatin/silica composite walls (several tens of nanometers in thickness), where the sol-gel derived silica bioglass phase was uniformly distributed throughout the gelatin matrix. The in vitro apatite-forming ability and biocompatibility of the nanofibrous gelatin/silica bioglass composite microspheres was significantly enhanced with an increase in silica content, demonstrating their great potential for the promotion of bone tissue regeneration.

Strong and Biostable Hyaluronic Acid-Calcium Phosphate Nanocomposite Hydrogel via in Situ Precipitation Process.

Hyaluronic acid (HAc) hydrogel exhibits excellent biocompatibility, but it has limited biomedical application due to its poor biomechanical properties as well as too-fast enzymatic degradation. In this study, we have developed an in situ precipitation process for the fabrication of a HAc-calcium phosphate nanocomposite hydrogel, after the formation of the glycidyl methacrylate-conjugated HAc (GMHA) hydrogels via photo-cross-linking, to improve the mechanical and biological properties under physiological conditions. In particular, our process facilitates the rapid incorporation of calcium phosphate (CaP) nanoparticles of uniform size and with minimal agglomeration into a polymer matrix, homogeneously. Compared with pure HAc, the nanocomposite hydrogels exhibit improved mechanical behavior. Specifically, the shear modulus is improved by a factor of 4. The biostability of the nanocomposite hydrogel was also significantly improved compared with that of pure HAc hydrogels under both in vitro and in vivo conditions.

Reinforcement of polyetheretherketone polymer with titanium for improved mechanical properties and in vitro biocompatibility.

Blends of ductile Ti metal with polyetheretherketone (PEEK) polymer were studied with regard to their mechanical properties and in vitro biocompatibility. PEEK/Ti composites with various Ti contents, ranging from 0 vol % to 60 vol %, were produced by compression molding at 370°C. In all composites produced, regardless of the initial Ti content, Ti particles were well distributed in the PEEK matrix. Addition of Ti led to a significant increase in mechanical properties of PEEK. Specifically, an increase in Ti content enhanced compressive strength and stiffness, while preserving ductile fracture behavior. In addition, the use of Ti for reinforcement of PEEK provided the composites with improved in vitro biocompatibility in terms of the attachment, proliferation, and differentiation of MC3T3-E1 cells.

Fabrication of Mechanically Tunable and Bioactive Metal Scaffolds for Biomedical Applications.

Biometal systems have been widely used for biomedical applications, in particular, as load-bearing materials. However, major challenges are high stiffness and low bioactivity of metals. In this study, we have developed a new method towards fabricating a new type of bioactive and mechanically reliable porous metal scaffolds-densified porous Ti scaffolds. The method consists of two fabrication processes, 1) the fabrication of porous Ti scaffolds by dynamic freeze casting, and 2) coating and densification of the porous scaffolds. The dynamic freeze casting method to fabricate porous Ti scaffolds allowed the densification of porous scaffolds by minimizing the chemical contamination and structural defects. The densification process is distinctive for three reasons. First, the densification process is simple, because it requires a control of only one parameter (degree of densification). Second, it is effective, as it achieves mechanical enhancement and sustainable release of biomolecules from porous scaffolds. Third, it has broad applications, as it is also applicable to the fabrication of functionally graded porous scaffolds by spatially varied strain during densification.

Production of porous Calcium Phosphate (CaP) ceramics with aligned pores using ceramic/camphene-based co-extrusion.

BACKGROUND: Calcium phosphate (CaP) ceramics are one of the most valuable biomaterials for uses as the bone scaffold owing to their outstanding biocompatability, bioactivity, and biodegradation nature. In particular, these materials with an open porous structure can stimulate bone ingrowth into their 3-dimensionally interconnected pores. However, the creation of pores in bulk materials would inevitably cause a severe reduction in mechanical properties. Thus, it is a challenge to explore new ways of improving the mechanical properties of porous CaP scaffolds without scarifying their high porosity. RESULTS: Porous CaP ceramic scaffolds with aligned pores were successfully produced using ceramic/camphene-based co-extrusion. This aligned porous structure allowed for the achievement of high compressive strength when tested parallel to the direction of aligned pores. In addition, the overall porosity and mechanical properties of the aligned porous CaP ceramic scaffolds could be tailored simply by adjusting the initial CaP content in the CaP/camphene slurry. The porous CaP scaffolds showed excellent in vitro biocompatibility, suggesting their potential as the bone scaffold. CONCLUSIONS: Aligned porous CaP ceramic scaffolds with considerably enhanced mechanical properties and tailorable porosity would find very useful applications as the bone scaffold.

Novel strategy for mechanically tunable and bioactive metal implants.

Metals have been used as biostructural materials because of outstanding mechanical reliability. However, low bioactivity and high stiffness in biological environments have been major issues of metals, causing stress shielding effects or foreign body reactions after implantation. Therefore, in this study, densified porous titanium has been introduced to achieve comparable mechanical properties to hard tissues and bioactivity that promote a better interface between the implant and bone. Porous titanium scaffolds were successfully fabricated through dynamic freezing casting, and were densified, controlling the degree of densification by applied strain. During densification, structural integrity of porous titanium was well maintained without any mechanical deterioration, exhibiting good pore connectivity and large surface area. Densified porous titanium possesses two important features that have not been achieved by either dense titanium or porous titanium: 1) mechanical tunability of porous scaffolds through densification that allows scaffolds to be applied ranging from highly porous fillers to dense load-bearing implants and 2) improved bioactivity through bioactive coating that is capable of sustainable release through utilizing high surface area and pore connectivity with controllable tortuosity. This simple, but effective post-fabrication process of porous scaffolds has great potential to resolve unmet needs of biometals for biomedical applications.