The definition of a GMO according to the EU directives [1, 2].
\\n\\n
Dr. Pletser’s experience includes 30 years of working with the European Space Agency as a Senior Physicist/Engineer and coordinating their parabolic flight campaigns, and he is the Guinness World Record holder for the most number of aircraft flown (12) in parabolas, personally logging more than 7,300 parabolas.
\\n\\nSeeing the 5,000th book published makes us at the same time proud, happy, humble, and grateful. This is a great opportunity to stop and celebrate what we have done so far, but is also an opportunity to engage even more, grow, and succeed. It wouldn't be possible to get here without the synergy of team members’ hard work and authors and editors who devote time and their expertise into Open Access book publishing with us.
\\n\\nOver these years, we have gone from pioneering the scientific Open Access book publishing field to being the world’s largest Open Access book publisher. Nonetheless, our vision has remained the same: to meet the challenges of making relevant knowledge available to the worldwide community under the Open Access model.
\\n\\nWe are excited about the present, and we look forward to sharing many more successes in the future.
\\n\\nThank you all for being part of the journey. 5,000 times thank you!
\\n\\nNow with 5,000 titles available Open Access, which one will you read next?
\\n\\nRead, share and download for free: https://www.intechopen.com/books
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'
Preparation of Space Experiments edited by international leading expert Dr. Vladimir Pletser, Director of Space Training Operations at Blue Abyss is the 5,000th Open Access book published by IntechOpen and our milestone publication!
\n\n"This book presents some of the current trends in space microgravity research. The eleven chapters introduce various facets of space research in physical sciences, human physiology and technology developed using the microgravity environment not only to improve our fundamental understanding in these domains but also to adapt this new knowledge for application on earth." says the editor. Listen what else Dr. Pletser has to say...
\n\n\n\nDr. Pletser’s experience includes 30 years of working with the European Space Agency as a Senior Physicist/Engineer and coordinating their parabolic flight campaigns, and he is the Guinness World Record holder for the most number of aircraft flown (12) in parabolas, personally logging more than 7,300 parabolas.
\n\nSeeing the 5,000th book published makes us at the same time proud, happy, humble, and grateful. This is a great opportunity to stop and celebrate what we have done so far, but is also an opportunity to engage even more, grow, and succeed. It wouldn't be possible to get here without the synergy of team members’ hard work and authors and editors who devote time and their expertise into Open Access book publishing with us.
\n\nOver these years, we have gone from pioneering the scientific Open Access book publishing field to being the world’s largest Open Access book publisher. Nonetheless, our vision has remained the same: to meet the challenges of making relevant knowledge available to the worldwide community under the Open Access model.
\n\nWe are excited about the present, and we look forward to sharing many more successes in the future.
\n\nThank you all for being part of the journey. 5,000 times thank you!
\n\nNow with 5,000 titles available Open Access, which one will you read next?
\n\nRead, share and download for free: https://www.intechopen.com/books
\n\n\n\n
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\r\n\tPolyimide is nowadays fully acknowledged as one of the most efficient polymers in many industries for its excellent thermal, electrical and mechanical properties, as well as for its easy processability. Particularly, in the Electronic and Electrical Engineering industries, polyimide is widely used for decades thanks to its very good dielectric and insulating properties at high electric field and high temperature up to 250°C in long term-service.
\r\n\t
\r\n\tSince its discovery in the mid-50’s, a wide range of applications from low to high voltage appeared, putting polyimide as a key material to design more performing and reliable electrical devices and systems. On another hand, polyimide appears also essential for the development of new electronic devices where further considerations such as high power density, integration, higher temperature, thermal conduction management, energy storage, reliability or flexibility are required in order to sustain the growing electrical energy consumption needs of the global society.
\r\n\tConsequently, polyimide materials have and will have to face new exciting fundamental, technological and environmental challenges among which:
\r\n\t• a better understanding of its intrinsic electrical properties to identify current limitations and propose new advanced device designs,
\r\n\t• the development of innovative composites and nanocomposites structuration to tailor its physical properties by involving classical and original nanoparticles such as graphene layer, carbon nanotubes, metal, silicates, nitrides, etc.,
\r\n\t• the development of polyimide composites for energy storage, thermal management, reinforced nanodielectrics and corona-resistant nanocomposites,
\r\n\t• the development of new low and ultra-low dielectric constant polyimide for microelectronics (fluorinated polyimides, nanoporous, mesoporous),
\r\n\t• the development of new higher temperature reliable polyimide (high glass transition, high degradation temperature),
\r\n\t• the emergence of solvent-free processes to fit with environmental purposes
\r\n\tMoreover, many challenges regarding the aging mechanisms understanding under single or multiple constraints and the realistic lifetime prediction using robust physical modelling is a ubiquitous questioning in most of the electronic industries.
\r\n\tThis book will target to review both the state-of-the-art and new researches on Polyimide for Electronic and Electrical Engineering Applications. It will present interdisciplinary chapters on the state of knowledge of each topic under consideration through a combination of overviews and original unpublished research. Chapter proposals related to one of the following topics and their keywords (but not only restricted to them) are very welcome to be submitted for this book publication project:
\r\n\t• General Considerations and Technological Processes of Polyimide for Electronics and Electrical Systems
\r\n\tProcessability, Photosensitive and non-photosensitive polyimide, Curing temperature,
\r\n\tSpin-coating, Dip-coating, Extruded enameled wires, Other casting methods
\r\n\t• Polyimide in Microelectronic Applications
\r\n\tDielectric properties, Intermetal layer, Ultra Large-Scale Integration (ULSI), Low-k dielectrics, Fluorinated polyimide, Nanoporous polyimide, Flexible substrates, Thin film transistors, LCD devices, sensors and actuators (gas, humidity, pressure, tactile…)
\r\n\t• Polyimide in Medium and High Voltage Applications
\r\n\tElectrical insulation properties (conduction, breakdown), Digital isolators, Power electronics and devices, Power modules, Power integration, Passivation, Packaging, High voltage power systems, Enameled wires for fed-inverter rotating machine
Compared with bulk semiconductors, 1D semiconducting nanowires possess some very unique properties such as quantum confinement effects, surface sensitivity, intrinsically miniaturized dimensions, and low leakage currents which make them attractive as building blocks for functional nanosystems and next generation electronics (Khanal et al., 2007; Andersen et al., 2007; Tilke et al., 2003, as cited in Wu, 2008; Huang et al., 2010). This can be inferred from the sharply increasing number of publications in this field. Figure 1 shows the number of publications on nanowires or nanowhiskers by year, determined from a CAS SciFinder search (Wang et al., 2006). Especially for Silicon Nanowires, there are more than 700 articles published in 2008, which is twice the number published in 2005 (Schmidt et al., 2010).
\n\t\t\t\tNumber of publications on Nanowires or Nanowhiskers by year, determined from CAS SciFinder search.
The earliest silicon wires were produced in the late 1950s as silicon whiskers (Treuting & Arnold, 1957, as cited in Schmidt et al., 2010). Nowadays, the term whisker has been almost displaced by the term wire and nanowire. Rodlike crystals with a diameter of less than 100nm will be referred to as nanowires while the term wire is used to the rodlike crystals of larger diameters (more than 100nm).
\n\t\t\tOver the past several years, great efforts have been placed on the bulk synthesis of one-dimensional nanoscale materials, and various synthesis methods, such as chemical vapor deposition (CVD) (Amelinckx et al., 1994, as cited in Huang et al., 2010), arc discharge, laser ablation (Thess et al., 1994; Morales & Lieber, 1998; Yu et al., 1998a; Yudasaka et al., 1997, as cited in Huang et al., 2010), template-assisted growth (Dai et al., 1995; Han et al. 1997a, 1997b, 1998, 1999; Zhang et al., 2000, 2001, as cited in Huang et al., 2010), physical evaporation (PE) (Yu et al., 1997b; Zhang et al., 1999; Zhang et al., 2000, as cited in Huang et al., 2010) and lithography (Giovine et al., 2001, as cited in Huang et al., 2010) have been exploited. The most prominent method for silicon nanowire synthesis is the VLS growth mechanism, which is firstly proposed in March 1964 by Wagner and Ellis.
\n\t\t\t\t\ta) Schematics of the vapor-liquid-solid growth mechanism. (b) Scanning electron micrograph of epitaxially grown Si nanowires on Si <111>. (c) Transmission electron micrograph of the interface region between Si nanowire and substrate. Note the epitaxy and the curved shape of the nanowire flank.
The name VLS mechanism reflects the pathway of Si, which coming from the vapor phase diffuses through the liquid droplet and ends up as a solid Si wire. The VLS mechanism represents the core of silicon wire research, though it does not only work for silicon wire but also for a much broader range of wire materials, such as Ge (Wang et al., 2006) and other Ⅲ-Ⅴnanowires (Mandl et al., 2011). The VLS growth process can be summarized in the following four steps (Givargizov, 1975, as cited in Schmidt et al., 2010): (1) mass transport of SiH4 from the gas phase to the Au surface; (2) reaction of SiH4 on the Au surface; (3) diffusion of Si through the Au–Si eutectic liquid phase; (4) crystallization of Si from the supersaturated Au–Si eutectic liquid. The VLS mechanism can best be explained on the basis of Au catalyzed Si wire growth on silicon substrates by means of chemical vapor deposition (CVD) using a gaseous silicon precursor such as silane. Different metal-Si alloy system posses characteristic phase diagrams, which will be elaborated in section 1.2.1.1. The Au-Si binary phase diagram possesses a melting point of the Au-Si alloy strongly depends on composition. If heating Au in the presence of a sufficient amount of Si, considering e.g. a Au film on a Si substrate, to temperatures above 363 °C, the melting point of Au-Si alloy of 19 atom % Si and 81 atom % Au, will result in the formation of liquid Au-Si alloy droplets as schematically depicted in Figure 2a. When a gaseous silicon precursor such as silane, SiH4, covered these Au-Si alloy droplets, the SiH4 will be catalyzed to solid Si in the droplet interface. A continuous supply silicon precursor leads Si consequently to the growth of wires with a Au-Si droplet at their tip. Figure 2b is an example of Au-catalyzed Si nanowires grown homoepitaxially on a <111> substrate via the VLS-mechanism and Figure 2c is the transmission electron micrograph proves the epitaxial relation between nanowire and substrate (Schmidt, 2005, as cited in Schmidt et al., 2010).
\n\t\t\t\t\tAs discussed above, the VLS nanowire growth mechanism is merely deduced from the fact that these nanowires generally have alloy droplets on their tips, while the direct evidence, however, is still lacking. A better understanding of the nanowire growth process in the vapor phase is necessary to pin down the growth mechanism and to be able to rationally control their compositions, sizes, crystal structures, and growth directions. P. Yang group (Wu et al., 2001) reported the real-time observation of semiconductor nanowire growth in an in-situ high temperature transmission electron microscope (TEM).
\n\t\t\t\t\tIn situ TEM images recorded during the process of nanowire growth. (a) Au nanoclusters in solid state at 500 °C; (b) alloying initiates at 800 °C, at this stage Au exists in mostly solid state; (c) liquid Au/Ge alloy; (d) the nucleation of Ge nanocrystal on the alloy surface; (e)-(f) Ge nanocrystal elongates with further Ge condensation and eventually a wire forms. (
\n\t\t\t\t\t\tFigure 3a-f shows a sequence of TEM images during the growth of a Ge nanowire in situ. This real-time observation of the nanowire growth directly mirrors the proposed VLS mechanism in Figure 4a. We have examined over 50 individual Au clusters during the in situ catalytic nanowire growth. In general, three stages (I-III) could be clearly identified.
\n\t\t\t\t\tAlloying process (Figure 3a-c). Au clusters remain in the solid state up to our maximum experimental temperature 900 °C if there is no Ge vapor condensation. This is confirmed by selected area electron diffraction on the pure Au clusters. With increasing amount of Ge vapor condensation and dissolution, Ge and Au form an alloy and liquefy. The volume of the alloy droplets increases, and the elemental contrast decreases (due to dilution of the heavy metal Au with the lighter element Ge) while the alloy composition crosses sequentially, from left to right, a biphasic region (solid Au and Au/Ge liquid alloy) and a singlephase region (liquid). This alloying process can be depicted as an isothermal line in the Au-Ge phase diagram (Figure 4b).
Nucleation (Figure 3d,e). Once the composition of the alloy crosses the second liquidus line, it enters another biphasic region (Au/Ge alloy and Ge crystal). This is where nanowire nucleation starts. Knowing the alloy volume change, we estimate that the nucleation generally occurs at Ge weight percentage of 50-60%. This value differs from the composition calculated from the equilibrium phase diagram which indicates the first precipitation of Ge crystal should occur at 40% Ge (weight) and 800°C. This difference indicates that the nucleation indeed occurs in a supersaturated alloy liquid.
Axial growth (Figure 3d-f). Once the Ge nanocrystal nucleates at the liquid/solid interface, further condensation/ dissolution of Ge vapor into the system will increase the amount of Ge crystal precipitation from the alloy. This can be readily accounted for, using the famous lever rule of phase diagram. The incoming Ge species prefer to diffuse to and condense at the existing solid/liquid interface, primarily due to the fact that less energy will be involved with the crystal step growth as compared with secondary nucleation events in a finite volume. Consequently, secondary nucleation events are efficiently suppressed, and no new solid/liquid interface will be created. The existing interface will then be pushed forward (or backward) to form a nanowire (Figures 3f,\n\t\t\t\t\t\t\t\t4b). After the system cools, the alloy droplets solidify on the nanowire tips. Their compositions were analyzed with energy-dispersive X-ray spectroscopy (EDAX), and it was found that the weight percentage of Ge matches qualitatively well with the estimated alloy composition at which first Ge nanocrystal nucleates.
a) Schematic illustration of vapor-liquid-solid nanowire growth mechanism including three stages (I) alloying, (II) nucleation, and (III) axial growth. The three stages are projected onto the conventional Au-Ge binary phase diagram (b) to show the compositional and phase evolution during the nanowire growth process. (
The direct observation of nanowire growth unambiguously confirms the validity of vapor-liquid-solid crystal growth mechanism at the nanometer scale and should allow us to rationally control the nanowire growth which is critical for their potential implementation into the nanoscale electronic and optoelectronic devices.
\n\t\t\t\t\tThe most remarkable feature of the VLS growth mechanism, however, is its universality. VLS growth works well for a multitude of catalyst and wire materials and, regarding Si wire growth, over a size range of at least 5 orders of magnitude; from wire diameters of just a few nanometers up to several hundred micrometers.
\n\t\t\t\t\tThe characteristic of VLS mechanism is the application of metal catalyst, which is generally selected by phase diagrams. Figure 5 is showing phase diagrams of different metal-Si alloy system. To formulate the requirement on the catalyst-Si binary phase diagram in a more abstract way, Si wire growth requires a nonhorizontal phase boundary over which one can push the catalyst-Si system to enforce the precipitation of a Si rich solid. The catalyst materials are classified into three different categories by the phase diagrams of metal-Si system: Type-A, Type-B, Type-C (Bootsma & Gassen, 1971, as cited in Schmidt et al., 2010), as shown in figure 6.\n\t\t\t\t\t
\n\t\t\t\t\tSchematic phase diagrams of different metal-Si systems. (a) Au-Si, (b) Al-Si, (c) Ag-Si, (d) Zn-Si, (e) Ti-Si, (f) Pd-Si (
Type-A catalysts are the Au-like metals. Their phase diagram is of the simple eutectic type; that is, it is dominated by a single eutectic point. This eutectic point is located at a Si composition of more than 10 atom % Si. Furthermore, type-A catalysts do not possess any metal-silicide phases. There are only three type-A metals: Al, Ag, and Au.
\n\t\t\t\t\tAu is the most convenient and effective catalyst due to its nontoxicity, chemical stability and availability. Au is available not only by evaporation, but by Au colloid nanoparticles. And Au doesn’t oxidize in air to make an in situ deposition unnecessary, which is a decisive advantage for the pregrowth sample preparation. The Au-Si phase diagram is of the simple eutectic type, with its dominant feature being a eutectic point at a composition of about 19 atom % Si, indicating that Si likes to mix with Au. The eutectic temperature is 363 °C, a quite remarkable reduction of melting temperature, which is 700 K lower than the melting point of pure Au and about 1050 K below the melting point of pure Si. The phase within the V-shaped region, visible in Figure 5a., is the liquid phase, the actual composition of which depends on the amount of Si supplied. For Au-Si alloy droplets on a Si substrate, Si is abundant, and the composition of such Au-Si droplets is therefore given by the position of the liquidus line on the Si side, i.e. the phase boundary on the right-hand side (rhs) of the liquid phase. If such Au-Si droplets on a Si substrate, held at temperatures above the eutectic temperature, are exposed to a Si precursor such as silane, SiH4, silane molecules will crack at the surface of the droplets, thereby supplying additional Si to the droplet. This additional Si supply causes an increase of the Si concentration in the droplet to a value greater than the equilibrium concentration. Considering the Au-Si phase diagram shown in Figure 5a., this means that, by switching on the silane, the Au-Si droplet system is pushed over the liquidus line; and the only way for the droplet to reduce the Si concentration is to precipitate a Si-rich solid. In general, the composition of such a Si-rich solid would be given by the nearest phase boundary on the Si side of the liquidus. Consequently, the droplet precipitates Si, which with time results in the growth of a wire (Schmidt et al., 2010).
\n\t\t\t\t\tThe drawback for Au is the contamination of the nanowires (Allen et al., 2008; Perea et al., 2006; Shchetinin et al., 1991) in the semiconductor industry. Because it is associated with deep-level defects in Si, leading to strongly enhanced carrier recombination. Metal impurities in semiconductors are generally known to affect the charge carrier lifetimes by facilitating charge carrier recombination. The recombination rate critically depends on the energy difference between the impurity level or levels and the band gap middle; the closer the impurity level is to the band gap middle, the more efficient it is as a recombination center. The use of metals with impurity levels close to the band gap middle, so-called deep levels, is therefore to be avoided.
\n\t\t\t\t\tAl, another Type-A catalyst, shows the closest similarity of Al-Si binary phase diagram (see Figure 5b) with Au-Si, excluding that the eutectic point of the Al-Si system is located at a higher temperature (577°C) and at a slightly lower Si concentration (12 atom%). So Al could catalyze the VLS growth of Si nanowires undoubtly. Osada et al. (Osada et al., 1979, as cited in Schmidt et al., 2010) demonstrated Al catalyzed VLS growth of crystalline Si wires in a CVD process using silane and applying temperatures of 580-700°C. Compared with Au, Al catalyst shows the great advantage that Al does not create deep level defects. The major drawback of the use of Al, however, is its oxygen sensitivity. Oxidation of the Al catalyst particle has to be prevented during the whole processing sequence, which clearly limits the usability of Al.
\n\t\t\t\t\tSilver is the second nongold, type-A catalyst. The Ag-Si system (see Figure 5c) possesses a single eutectic point (at 11 atom % Si and 836 °C) (Weber, 2002, as cited in Schmidt et al., 2010). Due to the high eutectic temperature, high process temperatures at around 1000 °C are required for Ag-catalyzed VLS growth of Si wires. So the high process temperature becomes the disadvantage of Ag catalyst, because the Ag catalyst did not evaporate completely under these conditions, as the vapor pressure of Ag reaches a value close to 10-2 mbar at 1000 °C, which is about 3 orders of magnitude larger than that of Au (Geiger et al., 1987, as cited in Schmidt et al., 2010 ).
\n\t\t\t\t\tType-B catalysts are the low Si solubility metals. Their phase diagrams also show a single dominant eutectic point but no silicide phases. In contrast to the type-A catalysts, the eutectic point is located at much lower Si concentrations, less than 1 atom % Si. Typical type-B catalysts are In, Ga, or Zn. The Zn-Si binary phase diagram is dominated by a single eutectic point at 420 °C and 0.02 atom % Si, shown in Figure 5d., and despite its high vapor pressure of 0.2 mbar at 420 °C, Zn has proven to be an effective catalyst material for VLS growth (Chung et al., 2000). However, the impurity levels of Zn in Si are basically as detrimental as those of Au in the view of the electronic properties. The only advantage of using Zn is that a potential Zn contamination of wafers or equipment can be removed more easily than a potential Au contamination.
\n\t\t\t\t\tGa or In as catalyst of VLS growth appears to be much more attractive than that of Zn from a vapor pressure point of view. At 500 °C, the vapor pressure of In is below 10-7 mbar, and the vapor pressure of Ga is even lower: 10-10 mbar (Schmidt et al., 2010). Moreover, In and Ga would also be attractive from an electronics point, as both would induce a p-type doping of the wires. In terms of phase diagrams, Ga and In show great similarities. The Si concentrations at the eutectic point (smaller 0.01 atom %) as well as the eutectic temperatures (Ga, 30°C; In, 156°C) are very low in both cases, and any reasonable CVD growth temperatures will be way above the respective eutectic temperature. Therefore In or Ga can be expected to produce similar Si nanowire results (Givargizov & Sheftal, 1971, as cited in Schmidt et al., 2010).
\n\t\t\t\t\tType-C catalysts are the silicide forming metals. Their phase diagram indicates the presence of one or more silicide phases. In addition, the lowest eutectic temperature is higher than 800°C. Typical type-C catalysts are Cu, Pt, or Ti. Here is showing based on Ti catalyst. Figure 5e schematically depicts the Si-rich half of the Ti-Si phase diagram. As indicated therein, Ti-Si possesses a eutectic point at 1330°C adjoining the pure Si side of the phase diagram, whose liquidus can be used for Si wire growth via the VLS mechanism. At growth temperatures below 1330°C, growth should theoretically proceed via the phase that at this temperature is neighboring the pure Si side. As one can see in Figure 5e, this would be TiSi2. Considering growth at 1000°C and starting from a Ti particle, this Ti particle will first transform into Ti5Si3 and then into Ti5Si4, which becomes TiSi, which will finally transform into TiSi2. Only once this transformation process is completed can Si wire growth start.
\n\t\t\t\t\tTo explain the one-dimensional growth of Si nanowires prepared via VLS, the generation of invisible charged nanoparticles during VLS is experimentally confirmed. In an effort to confirm whether charged silicon nanoparticles were also generated during the synthesis of Si nanowires by VLS, a differential mobility analyzer (DMA) combined with a Faraday cup electrometer (FCE) was connected to an atmospheric-pressure CVD reactor under typical conditions for Si nanowire growth, as shown in Figure 7 (Kim et al., 2010).
\n\t\t\t\t\tPeriodic table with potential catalyst metals classified according to their phase diagram. Type-A: phase diagram dominated by a eutectic point at a Si concentration >10%; no metal-silicide phase present. Type-B: phase diagram dominated by a eutectic point at a Si concentration <1%; no metal-silicide phases present. Type-C: phase diagram with one or more metal-silicide phases; eutectic points located at temperatures above 800 °C. Elements marked with superscript ion have a vapor pressure of more than 0.01 mbar at 300 °C (
Schematic of experimental setup for the measurement of charged nanoparticles generated during theVLS process (
To investigate the effect of the reactor temperature on the deposition of Si nanowires and on the formation of nanoparticles in the gas phase, the reactor temperature was varied from 900 to 1000 °C at a SiCl4/H2 molar ratio of 0.1 and a hydrogen flow rate of 5 sccm, with the total flow rate of nitrogen and hydrogen fixed at 1000 sccm, and in situ measurements of charged nanoparticles were carried out using a DMA-FCE system. The results show that as the reactor temperature was increased, Si nanowire growth is enhanced with increasing reactor temperatures within the examined temperature range, and the size distribution of both positively and negatively charged nanoparticles shifted to smaller particle sizes and the number concentration of charged nanoparticles increased. At reactor temperatures above 900°C, the number concentration of charged nanoparticles smaller than ~30 nm increased drastically. These results indicate that the decomposition of SiCl4 increased with increasing reactor temperature. Thus, nucleation and charging of nanoparticles in the gas phase are enhanced with increasing reactor temperature due to enhanced thermal decomposition of SiCl4.\n\t\t\t\t\t
\n\t\t\t\t\tFESEM images of Si nanowires at SiCl4/H2 molar ratios of (a) 0.05, (b) 0.1, (C) 0.15, and (d) 0.2 at a hydrogen flow rate of 5 sccm and a reactor temperature of 975°C (the scale bar is 500 nm) (
To examine the effect of the molar ratio of SiCl4/H2 on both Si nanowire growth and the size distribution of charged nanoparticles, the molar ratio of SiCl4/H2 was varied at a fixed hydrogen flow rate of 5 sccm and a reactor temperature of 975°C. Figure 8 shows the FESEM images of nanowires formed at different molar ratios of SiCl4/H2. As the ratio of SiCl4/H2 was increased, both the diameter and the length of the nanowires increased. As the ratio of SiCl4/H2 was increased from 0.05 to 0.1, the diameter increased from 24 to 35 nm, and the length and the density of the nanowires were also markedly increased. As the ratio SiCl4/H2 was further increased to 0.15 and 0.20, the diameter drastically increased to 61 and 65 nm, respectively. This result indicates that the ratio of SiCl4/H2 is an important parameter controlling the diameter and length of Si nanowires. Therefore, the size of the gold nanoparticles is not the only parameter that determines the diameter of the Si nanowires that grow on them.
\n\t\t\t\t\t\n\t\t\t\t\t\tFigure 9 shows the particle size distribution of positively (Figure 9a) and negatively (Figure 9b) charged nanoparticles generated at various SiCl4/H2 ratios. The size distribution of positively and negatively charged nanoparticles generated at a SiCl4/H2 ratio of 0.05 has a peak at 14.6 nm. As the ratio of SiCl4/H2 increased, the size distribution of both positively and negatively charged nanoparticles shifted to larger particle sizes and the number concentration of charged nanoparticles increased drastically. However, the peak diameter did not change considerably at a SiCl4/H2 ratio higher than 0.1. These results show that the ratio of SiCl4/H2 not only affects the growth behavior of Si nanowires but also affects the size distribution of charged nanoparticles.
\n\t\t\t\t\tSize distribution of (a) positively and (b) negatively charged nanoparticles at various molar ratios of SiCl4/H2 at a hydrogen flow rate of 5 sccm and a reactor temperature of 975 °C (
Similiarly, the hydrogen flow rate has a sensitive effect on the generation of charged nanoparticles as well as the growth behavior of Si nanowires. As the hydrogen flow rate was increased from 5 to 10 sccm, the number concentration of charged nanoparticles increased, but it decreased at the hydrogen flow rate of 15 sccm. Especially at a hydrogen flow rate of 15 sccm, where Si nanowires did not grow, charged nanoparticles below 40 nm were not detected.
\n\t\t\t\t\tThe formation mechanism of charged silicon nanoparticles generated during Si nanowire synthesis by VLS could be deduced that gas phase nuclei of silicon would be formed first and then these nuclei undergo surface ionization on any surface, such as thevquartz tube of the reactor (Kim et al., 2009b). The surface ionization of gas phase nuclei is very similar to the electrostatic charging or triboelectric charging that is experienced commonly in everyday life. The electrostatic charging shows that charging can occur even at room temperature. it is more probable that the charged nanoparticles, instead of individual atoms or molecules, produced in the VLS process, should interact with the catalytic gold particles to produce the Si nanowires. The electrostatic attraction between the charged nanoparticles and the conducting gold particles would be much stronger than that between the charged nanoparticles and the insulating native oxide of the silicon substrate. The nanoparticles carried by the gas flow have difficulty in landing on a surface because of the levitation force: the gas flow velocity is zero on the surface and increases away from the surface. For charged nanoparticles to land on any surface, the electrostatic attraction between charged nanoparticles and the surface should overcome this levitation force. It appears that the electrostatic attraction between charged nanoparticles and the conducting gold particles is larger than the levitation force, whereas the electrostatic attraction between charged nanoparticles and the native silicon oxide of the substrate or the silicon surface of nanowires is less than the levitation force. This might be why charged nanoparticles land preferentially on the conducting gold particles, leading to nanowire growth. When the rod-shaped silicon is formed with a gold nanoparticle at its tip, the charged silicon nanoparticles would be attracted to the gold tip more preferentially than to the side of the silicon rod, considering that the charged nanoparticles should have higher electrostatic attraction energy with the conducting gold nanoparticles than with the side of the semiconducting silicon rod.
\n\t\t\t\tPrecise control of the SiNW diameter strongly affects the electrical and optical properties of the nanowires (Brus, 1994). The diameter of each Si nanowire is largely determinded by the size of the catalyst particle and growth conditions. In general, Au colloids are used to define the diameter and position of the SiNWs. Au colloids are ideal seeds for controlling the SiNW diameter: They act as the seeding metal for nanowire growth by the VLS process, and Au colloids may be synthesized or obtained commercially with relatively narrow size distributions. Since each colloid seeds the growth for one nanowire, aligned nanowires can be grown with narrow size distributions approaching those of the seed particles. Hence, by seeding wire growth with colloids of different average size, the average diameter of the SiNW arrays could be precisely controlled (Cui et al., 2001; Wu et al., 2004).
\n\t\t\t\t\t\tUsing a thin polyelectrolyte layer, gold colloids are electrostatically attracted to and immobilized on the substrate to act as seeds for Si nanowires grown using the VLS-CVD method. The diameter of the colloids precisely controls the nanowire diameter. The colloid solution concentration controls the density of growth. Microcontact printing of the polyelectrolyte layer confines wire growth to patterned regions (Hochbaum et al., 2005). As seen in Figure 10b, d, and f. Size distributions of both colloids and nanowires were determined from TEM micrographs. SiNWs grown from Au colloids of 50 (56 ± 5.0), 30 (30 ±3.3), and 20 (20 ± 2.1) nm diameters were 93±7.4, 43± 4.4, and 39 ± 3.7 nm in diameter, respectively (Hochbaum et al., 2005).
\n\t\t\t\t\t\ta, c, e) Cross-sectional images of nanowire samples grown from 50, 30, and 20 nm (nominally) Au colloids, respectively. Scale bars are 1 μm. (b, d, f) Size distributions of Au colloids and resulting SiNW diameters. (g) High-resolution transmission electron microscopy image of a single crystalline Si nanowire. Scale bar is 3 nm (
The density of nanowire growth is also critical to device function. By varying the concentration of the seeding solution (using 50 nm Au colloids as example here), we were able to control the seeding density on the substrate surface. The graph in Figure 11 shows the relationship between nanowire growth density, as determined from SEM images, and dilution of the gold colloid stock solution. Wires were seeded with densities ranging over an order of magnitude, from ~0.1-1.8 wires/μm2. In general, a good 1-to-1 nanoparticle/ nanowire ratio can be achieved, although it was observed that optimal growth conditions varied slightly with nanowire seeding density.
\n\t\t\t\t\t\tSiNW growth density dependence on the relative concentration of the seeding solution. All colloid solutions were diluted from the same stock solution. Insets show typical nanowire growth at 4/5 (top left) and 2/5 dilution (bottom right). Scale bars are 1μm (
For both phenomenological studies and the implementation of practical applications of SiNWs, fabrication of regular arrays of Si wires, with precise control of the crystallographic orientation, dimension, and density will be of great value. For laser interference lithography, the ultimate achievable resolution equals to one-fourth of the laser wavelength (Solak, 2006).To overcome the limitation in achieving reliable diameter reduction by reactive ion etching (RIE) for the smaller dimensions, template-based methods offer access to a wide variety of nanowires with a broad diversity in composition and shape. As template material, most commonly substrates such as track-etched polycarbonate membranes (Azarian et al., 2009), mesoporous silica (Petkov et al., 2007) and porous anodic alumina membranes (Xiang et al., 2008; Gao et al., 2002) are used.
\n\t\t\t\t\t\tA porous anodic alumina (PAA) is a material characterized by a honeycomb pattern of nanometer-sized pores with uniform diameter and spacin (Masuda & Fukuda, 1995). The pores are formed during the electrochemical anodization of aluminum under controlled conditions; different self-ordering conditions yield pores of different diameters and spacing (Nielsch et al., 2002). They give easy access to self-organized pores with high aspect ratios and tunable pore sizes (Gao et al. 2002; Masuda & Fukuda et al., 1995; Krishnan & Thompson, 2007; Nielsch et al., 2000). These pores are then used as a molding system for the synthesis of the desired nanostructures (Xiang et al., 2010).
\n\t\t\t\t\t\tSchematic diagram of the fabrication method used for the PAA template-based growth of SiNWs. (a) Cross-section of PAA, (b) electro-deposition of Au within pores, (c) VLS growth of SiNWs out of membrane surface, (d) SiNW removal by mechanical agitation, (e) VLS growth of SiNWs within membrane, and (f) SiNW removal by wet etching of membrane (
Schematic diagram of the fabrication method used for the PAA template-based growth of SiNWs. (i) Transfer of the PAA mask on Si (111), (ii) evaporation of Au through the PAA pores, (iii) PAA removal, and (iv) growth of SiNWs from the patterned substrate.
The VLS growth of SiNWs inside the pores of an unsupported PAA template using SiH4 as the precursor gas has been completed (Bogart et al., 2005; Lew & Redwing, 2003; Zhang et al., 2001), as shown in Figure 12. Briefly, gold is electro-deposited inside a free-standing PAA membrane, and the Au loaded template is placed inside the VLS growth furnace where SiNWs with uniform diameter are grown inside the pores of the alumina film. Subsequently, the template is dissolved (Bogart et al., 2005). The disadvantage of this process is that produced SiNWs are unsupported. In order to overcome the production of unsupported nanowires, due to the preventing their integration into functional devices (Lombardi et al., 2006), evaporation of Au through the PAA pores have been applied to overcome the dispesrion of SiNWs after removal of PPA membrane, as shown in Figure 13 (Lombardi et al., 2006).
\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFigure 14 shows the ordered pattern of gold nanodots after the thermal evaporation step and PAA mask removal. The size and arrangement of the gold clusters closely match those of the PAA pores. The average diameter of the dots is 53 nm with a standard deviation of 7.2%. The SiNW density could be controlled by simply changing the acid etch of the PAA film yielding pores up to required diameter while keeping the distance between pores unchanged. As a result, the gold nanoparticle arrays are arranged in a highly ordered configuration reflecting the hexagonal pattern of the nanopores of the PAA mask. SiNWs with controlled dimensions and spacings are grown in a rather inexpensive manner with this approach over large areas (~7 mm × ~7 mm). Additionally, this fabrication method is capable of producing SiNWs with a packing density as high as 6 ×109/cm2, which could be achieved otherwise only with lithographic techniques, entailing serious limits for mass scale production of these nanomaterials.
\n\t\t\t\t\t\tOrdered arrays of Au nanodots evaporated through the nanochannels of the PAA mask. The clusters have an average diameter of 53 nm and a dot-to-dot distance of 100 nm. The height of the dots is 5 nm.
a) Schematic of PDMS patterning of Au colloids. Briefly, a PDMS stamp is molded to the relief pattern of a photoresist master. After curing the polymer, the stamp is removed from the master and “inked” with a solution of poly-L-lysine. The stamp pattern is transferred to the Si (111) substrate, which is then immersed in the Au colloid solution. The colloid-patterned substrate is grown using the conventional VLS-CVD synthesis, resulting in a corresponding pattern of SiNW arrays. (b) Cross-sectional SEM image of PDMS patterned SiNW growth, and (c) plane-view SEM image of the same. Scale bars are 1 μm (
A poly(dimethylsiloxane) (PMDS) stamp was made using a photoresist master of 2 μm lines with 2 μm separation, and the pattern was transferred to the substrate by previously established techniques (Hochbaum et al., 2005) (Figure 15a). The stamp was “inked” with the poly-L-lysine solution by the same method described above for deposition on the Si substrates. The polymer pattern was transferred to a Si wafer by placing the stamp on the substrate and heating at 70 °C for 5 min. The patterned substrate was immersed in the 50 nm Au colloid solution for a short time, such that colloids only adhered to the polyelectrolyte and not the bare Si. Nanowires were synthesized on these substrates by the same VLS method. The resulting growth, seen in Figure 15b and c, is strictly confined to the regions of poly-L-lysine deposition. The plane-view SEM image (Figure 15c) shows a small part of the pattern, which is consistent over several square millimeters - the extent of the stamped area that was immersed in the colloid solution. Thus, spatial control over SiNW growth was achieved by patterning regions of seed particles using microcontact printing.
\n\t\t\t\t\tThe VLS mechanism is a well established growth technology for SiNWs. Based on the VLS mechanism, the diameter, the density and the special arrays of SiNWs can be well controlled by careful selections of catalysts, the templates and the growth conditions. The future challenge is the controllable growth of SiNWs matching with the devices requirements, such as single SiNW growth in an ordered place, the uncontaminated SiNWs.
\n\t\t\tThe discovery of the strong Stokes shift between absorption and emission in Si nanostructures suggested that emission could be due to an interfacial radiative emission center (Song & Bao, 1997; Klimov et al., 1998; Iacona et al., 2000, as cited in Priolo et al., 2001). Moreover, the quantum confinement picture and the interfacial state model have been reconciled by demonstrating that a Si=O double bond introduces size-dependent levels (both for electrons and for holes) within the gap (Wolkin et al., 1999). According to this picture it is the radiative recombination of this electron–hole pair trapped at the Si=O double bond, the process responsible for the observed emission. This emission, however, is still nc size dependent, due to quantum confinement effects, thus explaining the observed blueshift. migration and trapping of excitons within nanostructures have been studied in both porous Si and Si nc formed by ion implantation (Pavesi, 1996; Linnros et al., 1999, as cited in Priolo et al., 2001). But Si nanocrystals emit light at room temperature in the range 700–1100 nm (Priolo et al., 2001, as cited in Priolo et al., 2001).
\n\t\t\t\tIn order to realize the Si based light emitter in the technologically important 1.5 µm range (Ennen et al., 1983, as cited in Suh et al., 2005), the Er-doping of Si has attracted great attention because of its promising future in the development of light-emitting diodes and lasers operating at a wavelength of 1.54 μm, which coincides with the absorption minimum of optical fibers (Park et al., 2005). The Er doping of Si nanocrystals (ncs) holds some promise for efficiently generating light emission, since Si nanocrystals in the presence of Er act as efficient sensitizers for Er ions (Polman, 1997; Seo & Shin, 2001; Schmidt et al., 2002; Iacona et al., 2002, as cited in Park et al., 2005).
\n\t\t\tEr is an important rare earth material for optoelectronic devices due to its luminescence wavelength at about 1540 nm, which coincides with a minimum loss in optical fibers. Er-doped nanocrystals of indirect-gap semiconductors like Si are being widely studied as they would open new possibilities for applications in optoelectronics and microelectronics, with the main advantage of being compatible with actual device technology. As shown (Coffa et al., 1994, as cited in Park et al., 2005) in the Auger excitation model, the electron–hole pairs are bound to Er-related states below the conduction band in Si ncs. The exactions can then recombine and thereby excite the Er ions with an excess energy to the difference between the bound state and the conduction band in Si ncs. When Er is introduced in the sample the Er–nc interaction is particularly strong. In this case the excited nc preferentially transfers its energy to the Er ion. The Er ion is excited in a high energy state and decays very rapidly in the first excited state (4I13/2). At this stage its energy is too small to be transferred back to the nc and the Er remains excited until the radiative emission occurs at 1.54 μm while the nc luminescence at around 800 nm is totally quenched (Kenyon et al., 1994; Fujii et al., 1997, 1998; Franzo` et al., 1999; Chryssou et al., 1999; Kenyon et al., 2000; Shin et al., 2000a; Franzo` et al., 2000; Kik et al., 2000, as cited in Priolo et al., 2001). Therefore in the presence of Er ions a transfer of the energy among Si nc is thought to be less probable (Priolo et al., 2001).
\n\t\t\t\tExcellent optical properties were obtained by using silicon-rich silicon oxide (SRSO), which consists of Si ncs embedded inside a SiO2 matrix (Kenyon et al., 1994; Fujii et al., 1997; Shin et al., 1998, as cited in Suh et al., 2005). By now, optical gain (Han et al., 2002, as cited in Suh et al., 2005) as well as efficient light-emitting diodes (Franzó et al., 2002, as cited in Suh et al., 2005) have been demonstrated using Er-doped SRSO. Theoretical calculation (Nishio et al., 2003) also showed that the radiative recombination rate for Amorphous Si quantum dots (a-Si QDs) is higher by two or three orders of magnitude than that for Si ncs indicating that better performance can be obtained when a 1.54-μm light source fabricated using an Er-doped a-Si QD structure is employed. However, isolation of Si ncs inside the SiO2 matrix makes current injection into SRSO difficult. Thus, SRSO-based LEDs generally require either very high voltages (Franzó et al., 2002, as cited in Suh et al., 2005) or very thin SRSO layers that can limit the light output (Irrera et al., 2002, as cited in Suh et al., 2005). Furthermore, excitation occurs via impact excitation by energetic carriers, which raises questions about the long-term reliability of such devices.
\n\t\t\tCompared with the isolation of Si nc, SiNWs have diameters in the range of 10-100 nm and with lengths exceeding 1 μm. Thus, Er-doped SiNWs may provide a very high areal density of Er3+ ions in the case of Er-doping. The ease of charge injection into, and transport along the SiNWs are expected to improve the photoluminescence (PL) intensity. Si/Er core-shell nanowires with erbium enriched at the surface (Wang & Coffer, 2002) were fabricated successfully via a VLS process, which is modified by passing the He through a bubbler (heated to ~144 °C) containing Er(tmhd)3 after SiH4 flow. This process results in introducing Er to the surface of SiNWs, as shown in Figure 16.
\n\t\t\t\tDetectable erbium emission at room temperature in a crystalline semiconductor is often difficult to achieve. But the anticipated Er3+ with Er3+ luminescence near 1.54 μm, associated with the (4I13/2) → (4I15/2) transition, is observed upon excitation at 488 nm, as shown in Figure 17. However, it is regretted that the Photoluminescence (PL) intensity is very weak.
\n\t\t\t\tA typical TEM image of a surface Er enriched Si wire (JEOL JEM-3010). Inset: SAED pattern from the center of the wire. EDX analysis for the marked three areas are presented: Si 96% (area 2), erbium concentration ~12% (area 3), erbium 53% and silicon 47% (area 1).
Room-temperature photoluminescence (PL) spectrum of Er surface-enriched Si nanowires after a vacuum anneal, demonstrating the near-IR emission near 1540 nm (λex ) 488 nm).
As above mentioned, the optimum location for Er3+ is not inside Si, but in the nanometer-thin oxide shell right next to Si (Shin et al., 2000b; Kimura et al., 2003; Stepikhova et al., 1997, as cited in Suh et al., 2005). This suggests that rather than trying to dope Si-NWs directly, it would be preferable to coat the Si-NWs with high-quality Er-doped silica in order to optically activate the Si-NWs. Er coated SiNWs are achieved by using sol-gel derived Er-doped silica. The sol-gel technique is a low-temperature route widely employed to prepare thin film for integrated optic devices, because it can offer the homogeneous thin films at molecular scale and control of chemical purity. In this system, the pre-produced SiNWs are embedded inside an Er-doped silicon oxide film.
\n\t\t\t\t\t\tRoom temperature PL spectra of the Si-NWs and pure Er-doped silica film, pumped with the wavelength of 473 nm. The inset shows the wavelength dependence of the PL peak intensities (
\n\t\t\t\t\t\t\tFigure 18 shows the room temperature PL spectra of the Si-NWs and the pure Er-doped silica thin film, pumped with the 473 nm line of an Ar laser. The 473 nm line was chosen because it is absorbed only by Si-NWs and not directly by Er3+ ions. Hardly any luminescence from the pure silica film is not observed. However, the pure silica film does show Er3+ luminescence when Er3+ ions can directly absorb the pump photons, as shown in the inset. The strong Er3+ luminescence at 1.54 µm from the Si-NWs indicates energy transfer from carriers in Si-NWs to Er3+ ions.
\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFigure 19 shows the effect of temperature on the integrated Er3+ PL intensities. The pure silica film was pumped using the 488 nm line of an Ar laser in order to directly excite the Er3+ ions. On the other hand, the Si-NWs were pumped using the 477 nm line of an Ar laser, which is not absorbed optically by Er3+ ions, in order to probe only those Er3+ ions that can be excited via carriers. The temperature dependence of Er3+ luminescence lifetimes are nearly identical, as is shown in the inset. The Er3+ luminescence lifetime from the pure silica film decreases from 13.6 to 11 ms as the temperature is raised from 25 to 300 K, while that from the Si-NWs decreases from 8.3 to 6.9 ms. Such complete suppression of thermal quenching of Er3+ luminescence cannot be due to any quantum effects of the large diameter of SiNWs (Suh et al., 2005). Given the identical temperature dependence of the Er3+ luminescence lifetime, the reduction of the Er3+ luminescence lifetime by Si-NWs is attributed to the effect of increased effective refractive index (Snoeks et al., 1995) rather than any degradation of the quality of sol-gel derived silica film. Thus, it could be ensured that the Er3+ ions excited via carriers generated in Si-NWs are actually in the sol-gel derived Er-doped silica film that is coating the Si-NWs (Shin et al., 2000b; Kimura et al., 2003; Stepikhova et al., 1997), indicating that Si-NWs, even without quantum confinement effects, are much more effective for exciting Er3+ ions in an oxide layer on their surface. This conclusion is supported by the low-temperature PL spectra, as shown in Figure 20. The 4I13/2→4I15/2 transition responsible for the 1.54 µm Er3+ luminescence is a parity-forbidden transition that occurs in part due to the effects of the crystal field, and the exact shape and position of the luminescence spectra depend on the chemical and structural environment of Er (Stepikhova et al., 1997).
\n\t\t\t\t\t\tThe temperature dependence of Er3+ integrated PL intensities, showing the complete suppression of thermal quenching. The inset shows the temperature dependence of the luminescence lifetimes.
Normalized PL spectra of pure Er-doped silica (488 nm), with Si-NWs (488 nm) and with Si-NWs (477 nm) at 25 K. The spectra are completely idenctical within the spectral resolution, indicating that the luminescent Er3+ ions are all in silica. The inset shows the schematic description of the proposed Er3+ luminescence.
Therefore, the results indicate that by using sol-gel derived Er-doped silica to optically activate Si-NWs, we can simultaneously achieve the ease of carrier injection, high carriermediated Er3+ excitation efficiency, and high Er3+ luminescence efficiency in a thick, easily produced film with a very high areal density of Er3+ ions, thus providing a promising material platform for Si photonics. The effectiveness of Si-NWs in enhancing the Er3+ luminescence can be increased by simply increasing the density of Si-NWs. Furthermore, because the growth of Si-NWs and its coating by sol-gel derived Er-doped silica are performed separately, the two processes can be optimized separately.
\n\t\t\t\t\tSiO2 derived from sol-gel was used as a precursor to disperse Er3+ ions. But the film is uncontinuous and the erbium ions gather to clusters, which may induce the concentration quenching of the photoluminescence (PL) intensity. In fact, the concentration quenching at high concentration of Er should be avoided to realize the strong luminescence of the devices.
\n\t\t\t\t\t\tAl2O3 is another promising material for high quality, low loss waveguide fabrication. Optical doping of thin Al2O3 films by Er ion implantation (van den Hoven et al., 1993, 1996) and by sol-gel technology (Feofilov, 1998; Patra, 2004) have been reported. Not only because the relatively high refraction index of Al2O3 (Al2O3, n=1.64 is higher than SiO2 (n=1.45)) (Wang & Lei, 2005) is expected to improve the optical transfer efficiency, but the similarity in valency and lattice constants between Al2O3 and Er2O3 may enable disperse high concentrations optical doping with Er (van den Hoven et al., 1993, 1996; Feofilov, 1998). Furthermore, Aluminium oxide possesses the low thermal expansion coefficient (Jaymes et al., 1996), high chemical durability, and good mechanical property, which are benefit to Al2O3 film derived from sol-gel solutions on Si wafer substrate. It is very important for the application of the optical devices (Jimenez de Castro et al., 2000; Wang et al., 2004a, 2004b; Armelao et al., 2005). In order to prevent the clustering of erbium ions in the silica network, Al ions could be added into the silicon oxide structure or completely aluminum oxide structure. Therefore, the optically harmful Er clustering could be prevented by the selective coordination of Al3+ around the Er3+ ions (Patra, 2004) allowing for a homogeneous dispersion of Er ions in the silicon oxide structure.
\n\t\t\t\t\t\tX-ray diffraction patterns of (A-a (Ren, 2008) and B-c (Ren et al., 2007a)) Er-doped SiO2 derived from sol-gel heat-treated at 750°C(Er/Si = 0.05), (A-b (
In order to understand the relationship between the PL properties and the structures of Er-doped Al2O3, Si and Al oxides complex (SiAlO) and SiO2 sol-gel films, the powder XRD patterns of heat-treated sol-gels at 750°C with compositions of Er-doped SiO2 (A-a and B-c), Er-doped SiAlO (B-d) and Er-doped Al2O3 (A-b) are tested, as shown in Figure 21 (Ren et al., 2007a, 2008). Figure 21 (A-a and B-c) shows the XRD pattern of Er-doped Si oxides. It shows the amorphous structure due to the short range ordering of Si network (Stepikhova et al., 2004). As shown in Figure 21 (B-d), the Er-doped Si–Al oxides also show an amorphous structure, indicating that the incorporation of Al into the Si network does not change the structures. However, it is expected that a more homogeneous incorporation of Er ions into Al–Si network compared to the Si network is likely by the selective coordination of Al3+ around the Er3+ ions. However, the Er3Al5O12 (PDFN 78-1451) phase and ErAlO3 (PDFN 24-0396) phase are observed as shown in Fig. 21(A-b), which is consistent with Tanner’s report (Kenyon, 2002) where the mixture of Er3Al5O12 and ErAlO3 are achieved for concentrations at or below 10% Er doped into Al2O3 due to the valence match between the rare-earth ions (Er3+) and the substituted cation (Al3+). As a result, it allows the incorporation of Er3+ into the Al2O3 lattice (Hochbaum et al., 2005) despite of the large size difference between Er3+ (0.89 nm) and the Al3+ (0.53 nm) (Tanner et al., 2004). It indicates that Er ions are homogeneous in Al2O3 even at high concentrations.
\n\t\t\t\t\t\tSEM images of (a) SiNW-ErAlO (
\n\t\t\t\t\t\t\tFigure 22 shows the SEM images of SiNW-ErAlO (a), SiNW-ErSiAlO (b) and SiNW-ErSiO (c) films. As shown in Figure 22, SiNW-ErAlO (a) and SiNW-ErSiAlO (b) film are continuous without cracks but numerous splits emerge in SiNW-ErSiO (c) film. A zoomed image further shows that the sol–gel solution has completely penetrated the SiNWs arrays, and had formed a crack-free, integrative film with tight SiNWs. The higher quality of film derived from Al–Si solution is due to the comparable thermal expansion coefficient of the film over that of the Si substrate. The thermal expansion coefficient of SiO2, Al2O3 and Si is 66 x 10-6/K, 23 x 10-6/K and 23 x 10-6/K, respectively. Thus, the cracks in the Er–Si oxide film are due to large differences in the thermal expansion coefficient between the SiO2 and the Si binary system. In addition, an addition of Al to the Si-oxide while maintaining its amorphous structures matches the thermal expansion coefficient of the film (55 x 10-6/K, according to the rule of mixture) to the Si substrate and suppressed the formation of cracks during the heat treatment. Thus, the reason of the high quality of SiNW-ErAlO and SiNW-ErSiAlO films are those the thermal expansion coefficient of the film over that of Si substrate matched well whereas the cracks in SiNW-ErSiO film are due to large differences in thermal expansion coefficient between the SiO2 and the Si binary system.
\n\t\t\t\t\t\tIn order to further understand the relationship between PL properties and the structures of Er-doped Al2O3 and SiO2 sol-gel films, the TEM of heat treated sol-gels at 750°C are tested. Figure 23 was TEM images of Er-doped SiO2 and Er-doped Al2O3. As shown in the inset of Figure 23a and\n\t\t\t\t\t\t\tFigure 23b, the Er-doped SiO2 is amorphous due to its out-of-order structure in long range but the Er-doped Al2O3 is crystal structure because the optically active Er3+ ion readily substitutes for aluminium ions occupying octahedral sites in alumina (Kenyon, 2002), which is consistent with the XRD results. As shown in Figure 23a and 23b, the cluster sizes of Er-doped SiO2 (about 300 nm) are much larger than that of Er-doped Al2O3 (≤100 nm), indicating that the dispersion of Al2O3 is better than that of SiO2.
\n\t\t\t\t\t\tTEM images and EDX of (a, c) Er-doped SiO2 derived from sol-gel heat-treated at 750°C, inset is the selected area electron diffraction (SAED) pattern of the particles; (b, d) Er-doped Al2O3 derived from sol-gel heat-treated at 750°C, inset is the SAED pattern of the particles (
Furthermore, the EDX results also show that Er ions are dispersed in the SiO2 and Al2O3, as shown in Figure 8c and 8d, the mol ratios of Er/Si and Er/Al are 0.064 and 0.088 respectively, which are close to the original mol ratios. As we have discussed that the crystal mixture of Er3Al5O12 and ErAlO3 created when Er ions are doped into Al2O3, but the Er-doped SiO2 is amorphous, and TEM images indicate that Er-doped Al2O3 clusters are much smaller than that of Er-doped SiO2 clusters. So it could be deduced that the dispersion of Er ions at high concentration in Al2O3 is better than that in SiO2.
\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFigure 24 shows the PL spectra of SiNW-ErSiO, SiNW-ErSiAlO and SiNW-ErAlO at the room temperature, pumped with the 477 nm line of an Ar laser. The 477 nm line was chosen because it is absorbed only by SiNWs and not directly by Er3+ ions (Suh et al., 2005), which is also confirmed by our result, as shown in Figure 24A-a. No peak is observed in Figure 24A-a when only Er-doped SiO2, Er-doped SiAlO or Er-doped Al2O3 without SiNWs is pumped with the 477 nm line. This ensures that Er3+ excitation occurs via carriers only, and represents an accurate simulation of the situation under current injection. However we observed strong Er3+ luminescence at 1534nm (the PL intensity is 66.3 a.u.) from the SiNW-ErSiO even with the high Er concentration (Er/Si = 0.05, concentration 9 at.%), indicating that SiNWs provide a very high areal density of Er and energy transfer from carriers in SiNWs to Er3+ ions dispersed in SiO2, as shown in Figure 24A-b. It can be seen that the Full Width at Half Maximum (FWHM) of the luminescence is about 40.5 nm. This emission band is very typical and is attributed to the Stark splitting of Er3+ embedded in an amorphous structure plus small additional inhomogeneous and homogeneous broadening (Polman et al., 1991). Similarly, a strong Er luminescence was observed 1.534 μm from the SiNWs coated with Er-doped Si–Al oxide, as shown in Figure 24B-d, indicating an energy transfer from carriers in the SiNWs to the Er3+ ions. In addition, it can be seen that the FWHM (full width at half maximum) of the luminescence is approximately 56 nm. This emission band structure is especially typical, and may be attributed to the Stark splitting of Er3+ embedded in the amorphous structure. It could also be attributed to the presence of many different environments for Er3+ ions in the binary Si–Al oxides. The broadening of the spectra suggests a wider and homogeneous distribution of Er3+ sites in the matrix. As a result, the PL intensities of SiNW-ErSiO and SiNW-ErSiAlO are similar except that the film quality of SiNW-ErSiAlO id better than that of SiNW-ErSiO after addition of aluminum sol-gel into that of Silicon sol-gel.
\n\t\t\t\t\t\tRoom temperature PL spectra of (A-a) (
However, the PL spectrum of SiNW-ErAlO is shown in Figure 24.A-c. Stronger Er3+ luminescence (the PL intensity is about 407.6 a.u.) at 1528 nm from the SiNW-ErAlO is observed, which is approximate six times higher than that of SiNW-ErSiO, indicating the concentration quenching is not obvious even at so high Er concentration (Er/Al = 0.1), and there is more energy transfer from carriers in SiNWs to Er3+ ions in Al2O3 medium. Perhaps the reasons include two aspects. One is that Er ions with high concentration in Al2O3 disperse better than Er ions in SiO2, which excludes the concentration quenching. The other is that Al2O3 has an even higher refraction index, so it couples more efficiently to semiconductor laser materials. And waveguides with smaller dimensions and tighter optical modes can be produced. Moreover, an obvious blue shift of luminescence peak occurs in Figure 24A-c and the FWHM is about 46.9 nm, which is wider than that of SiNWs coating with Er-doped SiO2. It is known that the main reason for the broadening is the local crystal field symmetry at the rare earth ion site and the luminescence spectra of Er-doped nanoparticles are depended on the host structure (Patra, 2004). The XRD results and SAED patterns have shown that the crystal mixture of Er3Al5O12 and ErAlO3 created when Er ions are doped into Al2O3, but the Er-doped SiO2 is amorphous, which change the local structure around Er3+ ions (d’Acapito et al., 2001). Perhaps these are the reasons of the blue shift of luminescence peak and broadening of FWHM.
\n\t\t\t\t\tAs mentioned, there is a fixed method for preparing Er-doped SiNWs as following processes. Firstly, sputtered Au nanoparticles were employed as the catalyst and the NWs’ growth proceeded through a vapor-liquid-solid (VLS) crystal growth mechanism. Then, the long SiNWs were dipped into Sol-gel solutions by surface coating with Er-doped silica or other materials. That is because the optimum locations for Er ions are not inside Si, but in the nanometer thin oxide shell right next to Si (Kimura et al., 2003; Shin et al., 2000b; Stepikhova et al., 1997). As a result, rather than trying to dope SiNWs directly, it would be preferable to coat the SiNWs with high quality, Er-doped oxides by sol-gel in order to optically activate the SiNWs. Lastly, the Er-doped SiNWs derived from sol-gel solution are sintered.
\n\t\t\t\t\tControlled growth of well-ordered Er-doped SiNWs is crucial, and would eliminate much of the processing associated with device fabrication. Selective growth of SiNWs via a VLS mechanism were achieved using an ion implantation mask, (Sood et al., 2006) lithographically defined regions of SiNW growth by thin film evaporation (Gangloff et al., 2004; Islam et al., 2004) and seeding colloids (Hochbaum et al., 2005). These methods employ expensive or complex processing techniques, but are unfit for the controlled growth of SiNWs and selective coating of Er-doped solutions at the same time.
\n\t\t\t\t\tHowever, combined sol-gel techniques and gold colloids, a simple technique to achieve patterned growth of SiNWs coating with Er-doped aluminous film is presented. The advantage of this method is that the growth of patterned SiNWs, the doping of Er ions and the sintered process are completed by one step. The Er-doped aluminium gels are calcined to be powders when SiNWs are grown by a VLS mechanism, removing sintered process, so the energy consume is reduced considerable (Ren et al., 2007). SiNWs grew from a solution-based precursor containing ASB (Al(O-sec-C4H9)3), hydrogen tetrachloroaurate (HAuCl4) and Erbium by VLS mechanism for optical activation. In this process, the functional materials, Au nanoparticles and Er ions, are all evenly dispersed in the sol-gel solution at the same time. Furthermore, ASB was selected as the precursor to disperse Er ions because of its relatively high refraction index (n =1.64) waveguides compared with SiO2 (n = 1.45), leading to efficient pumping and amplification (Wang & Lei, 2005), lower thermal expansion coefficient (Jaymes et al., 1996). And aluminum could also be either a network former, supplying non-bridging oxygen bonds, or an octahedral-coordinated network modifier (Ryu & Kim, 1995). Moreover, the solution-based precursor allows locating gold/Aluminium gel on any well-defined position on substrate by shadow mask, printing, or soft lithography methods, which could facilitate the integration of SiNWs for characterization and devices. Micropatterns of GeNWs have been grown in a high yield on sol-gel prepared gold/silica substrate by using shadow mask with the help of an additive agent to keep a continuous film (Pan et al., 2005).
\n\t\t\t\t\tSEM images of Si nanowires patterns grown from sol-gel prepared gold/Er-doped aluminous film by using TEM grids as the masks (a) the ordered arrays of Si nanowires (b) High-magnification image showing no unwanted nanowires grown in the interspaces (
High-magnification TEM image of an individual Si nanowire grown from sol-gel prepared gold/Er-doped aluminous film with a hemispherical Au nanoparticle located at the tip (
Figure 25 is a SEM image of SiNW pattern produced by using a G200 copper TEM grid as the mask. As shown in Figure 25(a), the ordered arrays are obtained. And there is no unwanted nanowires grown in the interspaces except the obtained nanowires in the square area as shown in Figure 25(b), indicating that the spatial resolution of the patterns can be well controlled by the resolution of the mask used. Moreover, the SiNWs are tipped with an Au nanoparticle (determined by energy-dispersive X-ray (EDX) spectroscopy) with diameter comparable to the connected nanowire (Figure 26), thus showing a typical VLS growth feature. This result suggests that the growth of SiNWs occurs through an Au particle-catalyzed VLS growth mechanism even the gold nanoparticles dispersed in sol-gel solution. In addition, the dense of nanowires could be controlled by the amount of gold nanoparticles, and the thickness of the gel film could also be adjusted through changing the ASB concentration. Moreover, other techniques such as soft lithography (Kind et al., 2000; Huang et al., 2000) and direct printing (Cassell et al., 2001) could also be used to print the gold-containing solution to a desired position on the substrate surface, which might facilitate the integration of Si nanowires into devices.
\n\t\t\t\t\tFigure 27 is the XRD pattern of the Er –doped aluminous sol-gel materials sintered at 900°C. The characteristic XRD pattern of Er3Al5O12 phase (PDF 78 1451) is observed, indicating that the Al3+ cations are substituted by the Er3+ rare-earth ions sintered at 900°C due to the valence match between the Er3+ ions and the substituted Al3+ ions, which is consistent with Tanner’s report (Tanner et al., 2004) where the mixture of Er3Al5O12 and ErAlO3 are achieved for concentrations at or below 10% Er doped into Al2O3 due to the valence match between the rare-earth ions (Er3+) and the substituted cation (Al3+). As a result, it allows the incorporation of Er3+ into the Al2O3 lattice (Hochbaum et al., 2005) despite of the large size difference between Er3+ (0.89 nm) and the Al3+ (0.53 nm) (Tanner et al., 2004)]. Moreover, the θ-Al2O3 phase (PDF 35 0121) were observed, which is consistent with former reports (Wang et al., 2004a, 2004b) that when the sintered temperature is at 900°C, the γ-Al2O3 transfer to θ-Al2O3 phase. In addition, the small peaks of the Er2O3 (PDF 77 0464) phase are also observed.
\n\t\t\t\t\tX-ray diffraction patterns of Er-doped aluminous film sintered at 900 ºC. The solid circle (●) represents Er3Al5O12 peaks; the solid square (■) represents Er2O3 peaks; the star (*) represents θ-Al2O3 peaks (
Room temperature PL spectra of SiNWs grown from sol-gel prepared gold/Er-doped aluminous film at 900 ºC, wave guide with 477 nm excitation from Ar+ laser. (a) no SiNWs (b) with SiNWs. The inset shows the schematic process of carrier transfer from SiNW to Er ion (
\n\t\t\t\t\t\tFigure 28 shows the room temperature PL spectra of Si nanowires patterned grown on sol-gel prepared gold/Er-doped aluminous film, pumped with the 477 nm line of an Ar laser at room temperature. The 477 nm line was chosen because it is absorbed only by NWs and not directly by Er ions (Suh et al., 2005). This ensures that Er3+ excitation occurs via carriers only, and represents an accurate simulation of the situation under current injection, which has been confirmed by our result, as shown in Figure 28a. No peak is observed in Figure 13a when only Er-doped Al2O3 without SiNWs is pumped with the 477 nm line. This ensures that Er3+ excitation occurs via carriers only, and represents an accurate simulation of the situation under current injection. Nevertheless, we observed strong Er3+ luminescence at 1534 nm (the PL intensity is 75 a.u.) from the SiNWs coating with Er-doped Al2O3 as shown in Figure 28b, indicating that energy transfer from carriers in SiNWs to Er3+ ions dispersed in Al2O3. The schematic process is shown in the inset, which suggests that SiNWs are more effective for exciting Er ions in an oxide layer on their surface.
\n\t\t\t\t\tHowever, when the Si nanowires patterned grown on sol-gel prepared gold/Er-doped aluminous film are excited by the 488 nm line of an Ar laser at room temperature, reflecting the 4I15/2 → 4F7/2 and 4I15/2 → 4H11/2, the PL intensity (about 550 a.u.) is improved largely as shown in Figure 29. It could be explained that the 488 nm line of an Ar laser could excite not only Si nanowires, but also the Er3+ ions directly. The schematic process is shown in the inset. As a result, the excited Er concentrations are increased, indicating that the optically excited and carrier-excited Er ions are all possible.
\n\t\t\t\t\tRoom temperature PL spectra of SiNWs grown from sol-gel prepared gold/Er-doped aluminous film at 900 ºC, wave guide with 488 nm excitation from Ar+ laser. The inset shows the schematic process of carrier transfer from SiNW to Er ion and excited Er ion directly (
Ge nanowires (GeNWs) is another promising nanowires due to its high carrier mobility and a small band gap (Gu et al., 2001; Wang & Dai, 2002). Germanium is also an important semiconducting electronic material with indirect band gap. Moreover, the direct-gap (0.88 eV) is close to its indirect gap (0.75 eV) in Ge, predicting that quantum confinement effects would appear more pronounced in Ge than Si. The optical activation of GeNWs doping with Er ions (Er-GeNWs) instead of SiNWs will also be achieved and the PL intensity at 1540 nm should be improved largely. But a major limitation is cooperative interactions, such as up conversion and fast energy migration between Er3+ ions, limiting emission efficiency at high Er concentration (Snoeks et.al.,1997). Ytterbium is widely used to improve the PL intensity of Er ions because Yb is a well-known sensitizer for the Er emission at 1540 nm due to fast energy transfer from the Yb ions to Er centers and no up conversion in Yb-Yb, and absorption band of Yb ions cover a broad extent from 850 nm to 1000 nm (Kozanecki et al., 1999, 2001).
\n\t\t\tThus coating the SiNWs/GeNWs with high quality, Er/Er:Yb doped oxides by sol-gel are produced in order to optically activate the SiNWs/GeNWs (Ren et al., 2007c). Figure 30 shows the scanning electron microscope (SEM) image of as-grown SiNWs (a), GeNWs (b) for further coating sol-gel solutions as substrate and Er:Yb-SiNWs (c) and Er:Yb-GeNWs (d). As shown in Figure 30(a), the dense arrays of straight SiNWs by VLS are well aligned. The SiNWs lie at an angle of about 60˚ from the surface normal, which are about 100 nm in diameter and 10μm in length. Similarly, we also obtained GeNWs with smaller than 100 nm in diameter and 10 μm in length in Figure 30(b). As shown in Figure 30(c)\n\t\t\t\tand 30(d), both films are continuous without any cracks. The sol-gel solution has completely penetrated into the SiNWs and GeNWs arrays, forming a crack-free, integrative film tight of NWs, even after sintered at 750°C, the film still keeps continuous and the NWs can also be seen well, indicating that Er and Yb ions dispersed in the oxide film derived from sol-gel solutions are continuous to coat the SiNWs/GeNWs with high quality. These are important for the applications of planar devices.
\n\t\t\tSEM image of (a) Er:Yb-SiNWs, (b) Er:Yb-GeNWs. Er:Yb codoped Si-Al oxides coating on NWs films heated at 750°Cderived from the sol-gel solution (Si/Al = 3:1) (
Room temperature PL spectra of Er:Yb codoped Si-Al oxides coating SiNWs film heat-treated at 750°C, wave guide with 477 nm excitation from an Ar+ laser. (Si/Al = 3:1) (a) Er:Yb codoped Si-Al oxides without SiNWs, (b) Er-SiNWs, (c) Er:Yb-SiNWs, the inset is the corresponding schematic route of optical activation of SiNWs (
\n\t\t\t\tFigure 31 shows the room temperature PL spectra of Er-SiNWs and Er:Yb-SiNWs sintered at 750°C, pumped with the 477 nm line of an Ar laser. The 477 nm line was chosen because it is absorbed only by NWs and not directly by Er and Yb ions (Suh et al., 2005). This ensures that Er3+ excitation occurs via carriers only, and represents an accurate simulation of the situation under current injection. As shown in Figure 31(a), hardly any luminescence from the Er or Er:Yb codoped SiO2-Al2O3 without SiNWs is observed, which is consistent with the previous report (Suh et al., 2005) that either Yb or Er ions are not excited by this 477 nm wavelength laser, or there is no energy transfer to Er ions. However, a strong Er3+ luminescence (PL intensity is about 60 a.u.) at 1534 nm from Er-SiNWs was observed as shown in Figure 31(b), indicating SiNWs are excited by 477 nm wavelength and energy transfer from carriers in SiNWs to Er3+ ions. Unimaginably, the PL intensity (57.8 a.u. at 1534 nm) of Er:Yb-SiNWs was affected weakly after codoping Yb with Er,15 as shown in Figure 29(c), indicating that energy transfer from carriers in SiNWs not to Yb ions but to Er ions only. This result further confirms that the pumped energy of 477 nm wavelengths is directly absorbed by SiNWs, not by Er or Yb ions, suggesting that the Yb ions are not sensitizer for the Er emission at 1534 nm after SiNWs take part in the optical excitation and energy transfer.
\n\t\t\tRoom temperature PL spectra of Er:Yb codoped Si-Al oxides coating GeNWs film heat-treated at 750°C, wave guide with 477 nm excitation from an Ar+ laser. (Si/Al = 3:1) (a) Er:Yb codoped Si-Al oxides without GeNWs, (b) Er-GeNWs, (c) Er:Yb-GeNWs, the inset is the corresponding schematic route of optical activation of GeNWs (
\n\t\t\t\tFigure 32 shows the room temperature PL spectra of Er-GeNWs and Er:Yb-GeNWs. The same result with Figure 31(a) is shown in Figure 32(a) that few luminescence from the Er or Er:Yb codoped SiO2-Al2O3 without GeNWs was observed. But strong Er3+ luminescence (PL intensity is about 106.5 a.u.) at 1534 nm from Er-GeNWs is observed as shown in Figure 32(b), which is approximate two times higher than that of Er-SiNWs in Figure 31(b), indicating more energy transfer from carriers in GeNWs to Er3+ ions than that of in SiNWs. Furthermore, the PL intensity of Er3+ (about 343.6 a.u.) at 1532 nm from Er:Yb-GeNWs as shown in Figure 32(c) increased three times higher than that of only Er-GeNWs in Figure 32(b) after codoping Yb ions with Er ions, and a blue shift of the luminescence peak occurs as the Yb ions were added, suggesting that energy transfer from carriers in GeNWs to Yb ions and Yb ions are the sensitizer for the Er luminescence at 1534 nm after GeNWs participate in the luminescence excitation.
\n\t\t\tThe reasons of the PL distinction between Figure 31 and Figure 32 are deduced. One is perhaps due to the quantum effect of SiNWs and GeNWs. As shown in Figure 30, the diameter of the GeNWs is smaller than SiNWs. As we known, the optical properties of a quantum-confined system strongly depend on its size. Another reason is perhaps due to the indirect band gap nature of Si and Ge semiconductors. In Figure 31, photons are absorbed by the SiNWs and promote an electron from conduction band (CB) to the valence band (VB). Then the recombination of the electron with a hole in the valence band gives the typical Si nc light emission at ~0.8 μm (corresponding to 1.5 eV) (Khriachtchev & Räsänen, 2005). Since the 1.5 eV couples well with the 4I9/2 level of the Er manifold, in presence of Er, the energy can be transferred to the Er ions to excite it (Franzo` et al., 2000), as shown in Figure 33A ((a)-(e)) . From this level, a rapid relaxation occurs to the 4I11/2 level with the subsequent emission of 0.98 μm photons or with a relaxation to the metastable level 4I13/2 and emission of photons at 1534 nm. For GeNWs, the recombination of the electrons with holes in the valence band gives the Ge nc light emission at the range of 0.9-2.3 eV (Kanemitsu et al., 1992; de Azevedo et al., 2005). Other wavelength besides 1.5 eV, such as 0.9 eV, could also couple well with the metastable 4I13/2 level of the Er manifold and emission of photons at 1534 nm (as shown in Figure 33B). These different wavelengths from GeNWs could excite more Er ions than single wavelength (1.5 eV) from SiNWs. As a result, the PL intensity of Er-GeNWs is much higher than that of Er-SiNWs (as shown in Figure 31(b) and Figure 32(b)).
\n\t\t\tThe optical properties of Er codoped with Yb further proved that the indirect gap nature of Si and Ge semiconductors decides the energy transfer between semiconductor and rare earth ions. If the nanowire diameter decides the optical property, the PL intensity of Er:Yb-SiNWs should improved than that of only Er-SiNWs due to the sensitizer of Yb to Er. Actually, the Yb ions have no any effects on the PL intensity of Er:Yb-SiNWs, because the 1.5 eV wavelengths from excited SiNWs cannot be absorbed by Yb ions, but only by Er ions. As a result, the Yb ions cannot be excited and the PL intensity of Er:Yb-SiNWs didn’t change compared with that of Er-SiNWs after Yb ions doped with Er ions coating on the SiNWs surface.
\n\t\t\tHowever, the Yb ions have great effects on that of Er:Yb-GeNWs. GeNWs emit not only 0.9 eV and 1.5 eV wavelengths to couple well with the metastable 4I13/2 level of the Er ions directly, but also 1.3 eV wavelengths, coupling well with the excited state of Yb3+-2F5/2 states. So the excited energy from Yb3+ can be transferred resonantly to the 4I11/2 level of Er3+. This excitation process is shown in Figure 3.4C. Moreover, Ge is well known to oxidize to form GeO and GeO2 in air on the GeNW surfaces (Tabet et al., 1999; Wang et al., 2004). These oxidations can be excited to emit a luminescence around 3.1 - 4.1 eV (Oku et al., 2000). Theses lights cannot be absorbed by Er ions but can be absorbed by Yb ions (Kozanecki et al., 1999). As a result of photon absorption, the Yb ion becomes excited its 2+ state, leaving a hole, hVB, in the valence band, which most probably is localized near Yb2+ ion. In the subsequent, Yb2+ + hVB recombination process Yb3+ is left in its excited 2F5/2 state, from which energy then can be transferred resonantly to the 2I11/2 level of Er3+ (Song et al., 2006). Hence, the PL intensity of Er:Yb-GeNWs is the total intensities of the three processes and it is higher than that of without Yb codoping. The blue shift of the luminescence peak further indicates that Yb ions take part in the energy transfer during the optical activation of Er:Yb-GeNWs. In summary, the optical activations of SiNWs and GeNWs are mainly dependent on the indirect gap nature of Si and Ge semiconductors. Stronger optical activation of Er:Yb-GeNWs is achieved.
\n\t\t\tSchematic of the mechanisms of optical activation of Er-doped and Er:Yb-codoped SiNWs and GeNWs. (A) Er-doped and Er:Yb-codoped SiNWs; (B) Er-doped GeNWs; (C) and (D) Er:Yb-codoped GeNWs (
Optical activations of Er doped Si ncs, SiNWs and GeNWs have been observed, but the PL intensity of Si ncs is weaker than those of SiNWs and GeNWs. So much progress has been made to improve the photoluminescence (PL) intensity; however, a challenging problem in Er-doped semiconductors is that only a small fraction of the excitation energy is transferred from ncs to Er ions. One of the major limitations is that isolated ncs cannot be efficiently addressed electrically. On this point, the successful optical activation of Er-doped SiNWs (Er-SiNWs) has been achieved. More important that the optimum location for Er3+ is not inside Si, but in the nanometer-thin oxide shell right next to Si. This gives us simple ways to dope the NWs with additional technologies, such as sol-gel method. Thus, this process avoids the fabrication of SiNWs with Er ions directly. The long length of SiNWs exceeding 1 μm overcomes the isolation of Si nc dispersed in the SiO2 and Al2O3 matrix to provide a very high areal density of Er ions. Moreover, the controlled growth of well-ordered Er-doped SiNWs has been achieved. The growth of patterned SiNWs, the doping of Er ions and the sintered process are completed in one step. The Er-doped aluminium gels are calcined to be powders when SiNWs are grown by a VLS mechanism, removing sintered process, so the energy consume is reduced. Similarly, the GeNWs posses the same result. Moreover, the rare earth Yb may improve the PL intensity of Er-doped GeNWs additionally.
\n\t\t\tIn the future, the additional technologies for Er doping are required more attentions. For sol-gel method, the sol-gel film quality is important, such as no cracks, homogeneous, no concentration quench, and so on.The challenging researches focus on how to further improve the film quality and fine control of the film thickness to match well with the actual requirements. In addition, the SiNW diameter also has great affection on the PL intensity. The controlled growth of Er-doped SiNWs with stable diameter and arrays are also good challenge.
\n\t\tRecent progress in disease comprehension combined with new technology performances creates novel opportunities for vaccine development in various health sectors. The last decade has seen a significant increase in the development of prophylactic medicines aiming at preventing infectious diseases or immunotherapeutic products to fight non-infectious diseases such as cancers. Both biopharmaceuticals are regarded as vaccines because they elicit an immune response, either against a pathogenic microorganism or against the host’s own tumour cells. Among these investigational medicinal products (IMP) for human use currently studied in clinical trials (CT), various candidate vaccines contain or consist of genetically modified organisms (GMOs). For the purpose of this chapter, this subset of IMPs will be further referred to as GMO vaccine candidates.
\nAs for any medicinal product, the clinical translation of research data is subject to a stringent regulatory framework, with procedures to ensure the quality, safety and efficacy of the product in humans. To conduct a new CT in one country of the European Union (EU), a clinical trial authorization must be obtained from the national competent authority, and the CT must be approved by an ethics committee. In the case of a CT involving a GMO vaccine candidate or any IMP containing or consisting of a GMO, an authorization should also be compliant with the provisions of the legislation regarding the use of GMOs.
\nWith the increasing number of authorization requests for CT with a GMO vaccine candidate and the new techniques that emerge for the construction of GMOs, the applicants, the national competent authorities and the different advisory bodies are facing some hurdles that may hamper the initiatives undertaken in the clinical translation of vaccine development in Europe. A first challenge originates from the several legislations with which the conduct of a CT with a GMO should comply in the country where the CT is planned. Different legislations are often under the control of different institutional bodies that may not necessarily interrelate and that may not be easily identified by applicants (see the example of Belgium in Figure 1). To a lesser extent, the obligation to follow distinct procedural regulations and the subsequent administrative burden may be a deterrent for them. Similarly, the applicant who plans to undertake a CT with a GMO vaccine candidate in multiple member states of the EU can be confronted with an equal number of country-specific procedures. Indeed, contrary to the standard CTA and ethics committee approval procedures for a CT, national GMO regulatory frameworks are not fully harmonized across the EU, and procedures for application may differ from one country to another. Finally, along with the emergence of new techniques intended for genetic modification, both applicants and authorities or advisory bodies are confronted with an increasing number of questions with respect to the interpretation of the definition of a GMO as laid down in the European GMO legislation.
\nOverview of Belgian regulatory framework for clinical trials involving an investigational medicinal product containing or consisting of GMOs. STA, scientific and technical advice; FAMHP, Federal Agency of Medicines and Health Products; CU, contained use; DR, deliberate release; EC, Ethics Committee; CTA, clinical trial application. (1) The FAMHP offers to the applicant the possibility to request a STA prior to other mandatory procedures. The STA provides clarity on the GMO status of the IMP involved and the mandatory procedures to follow. (2) The CU procedure is applied to activities with the GMO vaccine candidate taking place in a ‘contained’ facility. The regional authorities and Sciensano as the advisory body are involved in the CU procedure. The CU procedure and approval are independent of those also associated to a clinical trial. (3) The DR procedure is required when there is a probability of possible release of the GMO into the environment during the clinical trial. An application is submitted to the competent authority, the FAMHP. The application is evaluated by the advisory body (Biosafety Advisory Council) which transmits its advice to the FAMHP. An application under DR framework does not exempt an application under the CU procedure. (4 and 5) Following the national law of 7 May 2004 related to experiments on human, a clinical trial cannot start without a positive advice of the (leading) ethics committee and competent authority.
These challenges have the merit of prompting the debate between the different actors and to initiate exchanges at national and European level with the aim to foster a continued dynamic in innovative research, while ensuring the safety of human health and environment. By means of several examples, this book chapter illustrates several aspects of the implementation of the GMO legislation that are of relevance to CTs with a GMO vaccine candidate. The current state of discussions, an analysis of some of the hurdles that may hamper a smooth clinical translation as well as different options that are available to applicants are reviewed with respect to the Belgian and European regulatory frameworks.
\nThe European legislation on GMOs consists of two main Directives covering the use of genetically modified microorganisms (GMMs) in a contained facility (Directive 2009/41/EC) [1] and the deliberate release of GMOs into the environment (Directive 2001/18/EC) [2]. These Directives are mainly aimed at protecting the general population and the environment from potential risks arising from the use of GMMs and GMOs.
\nAccording to these Directives GMOs and GMMs are defined as organisms, with the exception of human beings, in which the genetic material has been altered in a way that does not occur naturally by mating and/or natural recombination. The definition of a GMO is both technology and process oriented: an organism will fall under the scope of the GMO regulations if it has been developed with the use of certain techniques. Therefore the EU Directives include annexes supplying information regarding the techniques that result in genetic modification, those that are not considered to result in genetic modification or those that result in genetic modification but yield organisms that are excluded from the scope of the directives (Table 1).
\nDirective 2009/41/EC | \nDirective 2001/18/EC | \n
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(a) ‘micro-organism’ means any microbiological entity, cellular or non-cellular, capable of replication or of transferring genetic material, including viruses, viroids, animal and plant cells in culture; (b) ‘genetically modified micro-organism’ (GMM) shall mean a micro-organism in which the genetic material has been altered in a way that does not occur naturally by mating and/or natural recombination. Within the terms of this definition: (i) genetic modification occurs at least through the use of the techniques listed in Annex I, Part A; (ii) the techniques listed in Annex I, Part B, are not considered to result in genetic modification; […] this Directive shall not apply: - where genetic modification is obtained through the use of the techniques/methods listed in Annex II, Part A | \n(1) ‘organism’ means any biological entity capable of replication or of transferring genetic material; (2) ‘genetically modified organism (GMO)’ means an organism, with the exception of human beings, in which the genetic material has been altered in a way that does not occur naturally by mating and/or natural recombination; Within the terms of this definition: (a) genetic modification occurs at least through the use of the techniques listed in Annex I A, Part 1; (b) the techniques listed in Annex I A, Part 2, are not considered to result in genetic modification. This Directive shall not apply to organisms obtained through the techniques of genetic modification listed in Annex I B. | \n
Techniques of genetic modification referred to in Article 2(b)(i) are, (1) Recombinant nucleic acid techniques involving the formation of new combinations of genetic material by the insertion of nucleic acid molecules produced by whatever means outside an organism, into any virus, bacterial plasmid or other vector system and their incorporation into a host organism in which they do not naturally occur but in which they are capable of continued propagation. (2) Techniques involving the direct introduction into a micro-organism of heritable material prepared outside the micro-organism including micro-injection, macro-injection and micro-encapsulation. (3) Cell fusion or hybridisation techniques where live cells with new combinations of heritable genetic material are formed through the fusion of two or more cells by means of methods that do not occur naturally. | \nTechniques of genetic modification referred to in Article 2(2)(a) are (1) Recombinant nucleic acid techniques involving the formation of new combinations of genetic material by the insertion of nucleic acid molecules produced by whatever means outside an organism, into any virus, bacterial plasmid or other vector system and their incorporation into a host organism in which they do not naturally occur but in which they are capable of continued propagation; (2) Techniques involving the direct introduction into an organism of heritable material prepared outside the organism including micro-injection, macro-injection and micro-encapsulation; (3) Cell fusion (including protoplast fusion) or hybridisation techniques where live cells with new combinations of heritable genetic material are formed through the fusion of two or more cells by means of methods that do not occur naturally. | \n
Techniques referred to in Article 2(b)(ii) which are not considered to result in genetic modification, on condition that they do not involve the use of recombinant-nucleic acid molecules or GMMs made by techniques/ methods other than techniques/methods excluded by Annex II, Part A: (1) (2) natural processes such as: conjugation, transduction, transformation; (3) polyploidy induction. | \nTechniques referred to in Article 2(2)(b) which are not considered to result in genetic modification, on condition that they do not involve the use of recombinant nucleic acid molecules or genetically modified organisms made by techniques/methods other than those excluded by Annex IB: (1) (2) natural processes such as: conjugation, transduction, transformation, (3) polyploidy induction. | \n
Techniques or methods of genetic modification yielding micro-organisms to be excluded from the Directive on the condition that they do not involve the use of recombinant-nucleic acid molecules or GMMs other than those produced by one or more of the techniques/methods listed below: (1) Mutagenesis. (2) Cell fusion (including protoplast fusion) of prokaryotic species that exchange genetic material by known physiological processes. (3) Cell fusion (including protoplast fusion) of cells of any eukaryotic species, including production of hybridomas and plant cell fusions. (4) Self-cloning consisting in the removal of nucleic acid sequences from a cell of an organism which may or may not be followed by reinsertion of all or part of that nucleic acid (or a synthetic equivalent) with or without prior enzymic or mechanical steps, into cells of the same species or into cells of phylogenetically closely related species which can exchange genetic material by natural physiological processes where the resulting micro-organism is unlikely to cause disease to humans, animals or plants. Self-cloning may include the use of recombinant vectors with an extended history of safe use in the particular micro-organisms. | \nTechniques/methods of genetic modification yielding organisms to be excluded from the Directive, on the condition that they do not involve the use of recombinant nucleic acid molecules or genetically modified organisms other than those produced by one or more of the techniques/methods listed below are: (1) mutagenesis, (2) cell fusion (including protoplast fusion) of plant cells of organisms which can exchange genetic material through traditional breeding methods. | \n
The GMO aspects of clinical trials with medicinal products containing or consisting of GMOs, including GMO vaccine candidates, are governed by national procedures implementing the GMO Directives. However, not all member states have the same approach in implementing provisions relating to deliberate release (DR) into the environment (Directive 2001/18/EC) and/or contained use (CU) (Directive 2009/41/EC) in the specific case of clinical trials. A first report on the approaches adopted by several member states in this matter has been commissioned by the European Commission (EC) and dates back to 2007 [3]. In 2018, recognizing the developments in novel medicinal products and the need of applicants of investigational products to have an up-to-date overview of regulatory requirements, a repository of national requirements was created [4]. The approaches adopted by Bulgaria, Germany, Hungary, Ireland, Slovakia, Slovenia, Spain, Sweden and the Netherlands on the one hand, and those prevailing in Denmark on the other, illustrate two extremes. In the first mentioned member states, only the ‘‘Deliberate Release’ framework is used to assess and manage the risks for human health and the environment, while in Denmark the biological confinement of medicinal products containing or consisting of GMOs and their use in controlled hospital environments trigger the application of the ‘Contained Use’ regulatory framework only.
\nOne of the important differences between Directive 2009/41/EC and Directive 2001/18/EC is that the latter requests the applicant to submit an environmental risk assessment (ERA). An ERA implies an assessment of the environmental impact of the GMO with regard to the potential risks for human health and the environment. Purely medical aspects concerning the efficacy of the IMP and its safety for the treated patient, as well as aspects related to social, economic or ethical considerations, are outside the scope of the ERA report. The ERA methodology for GMOs developed over the past decades is largely harmonized in many legislative systems and comprises the following steps: (1) hazard identification, (2) hazard characterization, (3) assessment of likelihood, (4) risk estimation and (5) evaluation of risk management options followed by (6) a conclusion on the acceptability (or not) of the overall impact of the use of the GMO on human health and the environment, taking into account the management strategies applied. Another feature of Directive 2001/18/EC is the mandatory public consultation.
\nIn the context of a marketing authorization application (MAA), it is important to note that Regulation (EC) No 726/2004 [5] laying down procedures for authorization and supervision of medicinal products requests an ERA similar to the ERA applied under Directive 2001/18/EC for medicinal products containing or consisting of GMOs. In practice, the scientific evaluation of the GMO, like any other MAA, is performed through a centralized authorization procedure across the EU. During this process, the European Medicines Agency holds consultations with the competent authorities (CA) of each member states established under Directive 2001/18/EC with respect to the evaluation of the environmental risk aspects. Therefore, even though a contained use-only procedure may have been accepted for a CT involving a GMO, an ERA will need to be submitted according to the provisions of Regulation (EC) 726/2004 should the IMP reach MAA.
\nIn Europe, Belgium is one of the most active countries in terms of CTs undertaken with GMO vaccine candidates [6]. This is also observed by the total number of requests submitted to the Belgian authorities for new CTs involving an IMP containing or consisting of a GMO from 2009 to 2018 (Figure 2). Until 2018, the number of requests registered annually remained relatively stable, after which a marked increase was observed. These applications involve CT with IMP containing or consisting of a GMO developed against infectious diseases or cancer, as well as CT with GMOs aiming to treat cardiovascular, autoimmune or hereditary diseases, gastrointestinal disorder or inflammation. Among all these IMPs, around 70% consist of GMO vaccine candidates for prophylactic or therapeutic purposes (data not showed).
\nNumber of new clinical trials involving an investigational medicinal product containing or consisting of GMOs since 2009 to 2018 in Belgium. A new clinical trial with a GMO can take place in different clinical centres at the same time. The investigational medicinal product can be directed against infectious, cardiovascular, autoimmune or hereditary diseases but also gastrointestinal disorders, inflammation or cancer.
GMO vaccine candidates are mainly composed of viral vectors containing one or more specific genetic sequences whose expression in the human body will enhance the immune response against an infectious agent or tumour cells (Figure 3). Recently, an increasing number of clinical studies have been realized using autologous or allogenic immune cells that have been genetically modified
Types of GMOs used as investigational medicinal products in clinical trials carried out in Belgian clinical centres and corresponding percentage of the total requests from 2009 to 2018. Globally, three main types of GMOs are used: autologous or allogeneic human cells that have been genetically modified ex vivo and reintroduced in a human body (blue), viral vectors genetically modified to carry the gene sequence of interest (orange) and attenuated derivatives of microorganisms that can operate as vaccines (grey).
In Belgium a clinical trial with an IMP containing or consisting of a GMO can fall into the framework of the CU only or the CU and DR legislations. The GMO procedural pathway is chosen and applied on a case-by-case basis in order to guarantee proportionate and scientifically robust evaluations. To aid in the determination of the legal procedure(s), the applicant is invited to evaluate if at any stage of the CT, the general population and the environment can be exposed to the IMP.
\nIn case physical barriers, or a combination of physical barriers together with chemical and/or biological barriers, are used to limit the contact with the general population and the environment, the CT and related activities have to comply with the Belgian legislation on CU of GMOs. Generally, activities such as the preparation, administration or storage of the IMP should follow the CU procedure only.
\nIn general, a CU procedure suffices when there is no possible release of the GMO in the environment (e.g. the GMO is administered in clinical centres only, and there is no spreading of the GMO when subjects leave the centre) or if proper management procedures and/or working practices are implemented to prevent such a release. On the contrary, when there is a probability of release into the environment (e.g. the subject leaves the clinical centre, and close contacts of the subject may become exposed to the GMO) which cannot be avoided by proper management procedures or working practices, a notification according to the DR procedure will additionally be required, and an ERA should be performed. Considerations that are taken into account to determine if a DR notification is needed are the probability of shedding of the GMO, hazards associated to the shedding should it occur, probability of spreading, or whether the GMO is also taken (administered) at home. Procedures for clinical trials within the DR framework are perceived as more cumbersome than those under CU, both for the applicants and for the governmental institutions that are reviewing the applications.
\nFor many human infectious diseases no satisfactory vaccine is currently available. Hence, public health needs are continuous incentives for further research and development. Scientific advances not only contributed to the development of novel vaccines that trigger the immune system for prophylactic purposes against infectious diseases but also offered opportunities in gene transfer for (cancer) immunotherapy and the treatment of tumours. Numerous examples have reached clinical development and in some cases even commercialization, even though the interpretation and/or implementation of the regulatory maze is often regarded as challenging by applicants. This section discusses recent developments illustrating the unique features and challenges for GMO vaccines with respect to the current GMO regulation.
\nDengvaxia is a GMO vaccine that recently obtained marketing authorization in the EU. This live attenuated vaccine is indicated for the prevention of dengue disease caused by dengue virus serotypes 1, 2, 3 and 4 in individuals living in endemic areas. The vaccine was developed using the attenuated yellow fever vaccine strain as a vector, which has been genetically modified to express the prM and E genes from the four different dengue virus serotypes. The administered vaccine thus contains four different virus constructs, each of which contains the prM and E genes from a different dengue virus serotype. Dengue is by far the most common mosquito-borne viral disease. It is transmitted by Aedes mosquitoes and infects people worldwide (mainly in tropical areas). Tens of millions of cases occur each year resulting in approximately 20,000–25,000 deaths, mainly in children [8]. Because four serologically distinct dengue viruses coexist in dengue-endemic areas, several dengue infections are possible during the patient’s lifetime.
\nThe ERA, conducted according to the principles laid down in Directive 2001/18/EC, included among others a consideration of the severity and likelihood of recombination or mutational events that would change the attenuated phenotype of the viral vector to one of virulence. The capacity of the GMO to replicate, disseminate and be transmitted by the Aedes mosquitoes was also evaluated. In addition, both shedding data of subjects receiving the recombinant viruses and the probability of mosquitoes or ticks transmitting the recombinant virus after oral feeding were considered in order to assess the likelihood of dissemination in the human population.
\nAnother aspect that was considered in the context of Directive 2001/18/EC is the detection, traceability and labelling of GMOs. These legal aspects have been further regulated into sectoral legislation for genetically modified food and feed as part of their EU authorization procedure (Regulation EC 1829/2003) [9], and several recommendations have been issued on how analysis methods should be evaluated and validated by the EU Reference Laboratory for Genetically Modified Food and Feed (EURL GMFF). Though Directive 2001/18/EC also covers IMP containing or consisting of GMOs, no sectorial legislation has been developed for IMP. Instead, as Regulation 726/2004, Art 6 (2), refers to Annex IV of Directive 2001/18/EC, traceability must be ensured at all stages of the placing on the market of GMOs (Table 2). However, compared to traceability requirements of genetically modified food and feed, it should be noted that much less experience has been gained so far with the validation of methods for the traceability of medicinal GMOs and no such laboratory network has been established to enforce traceability requirements at the European level. During the evaluation of the marketing authorization application of Dengvaxia, it was noticed that traceability methods proposed by the applicant referred to control and monitoring approaches for potentially contaminated effluents at manufacturing sites. However such methods are usually not adapted nor validated for detecting transfer of the donated genetic material to other organisms because the matrix in which the GMOs are supposed to be detected usually differ from those such as effluents of manufacturing sites.
\nRegulation (EC) 726/2004 | \nDirective 2001/18/EC | \n
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In the case of a medicinal product for human use containing or consisting of genetically modified organisms within the meaning of Article 2 of Directive 2001/18/EC, the application shall be accompanied by: (a) a copy of the competent authorities’ written consent to the deliberate release into the environment of the genetically modified organisms […]; (b) the complete technical dossier supplying the information required by Annexes III and IV to Directive 2001/18/EC; (c) the environmental risk assessment in accordance with the principles set out in Annex II to Directive 2001/18/EC; and (d) the results of any investigations performed for the purposes of research or development. | \nThis Annex describes in general terms the additional information to be provided in the case of notification for placing on the market and information for labelling requirements regarding GMOs: Information on the genetic modification for the purposes of placing on one or several registers modifications in organisms, which can be used for the detection and identification of particular GMO products to facilitate post-marketing control and inspection. This information should include where appropriate the lodging of samples of the GMO or its genetic material, with the competent authority and details of nucleotide sequences or other type of information which is necessary to identify the GMO product and its progeny, for example the methodology for detecting and identifying the GMO product, including experimental data demonstrating the specificity of the methodology. Information that cannot be placed, for confidentiality reasons, in the publicly accessible part of the register should be identified. | \n
Legal requirements regarding traceability of an IMP containing or consisting of a GMO in the case of notification for placing on the market.
One of the new avenues to develop novel types of vaccines is the plasmid-based live attenuated virus technology [10]. Upon identification of the protective antigen, this next-generation vaccine platform technology potentially provides for a rapid, versatile and cost-effective vaccine response platform to infectious diseases. The technology circumvents the manufacturing of free live attenuated viral particles as such, which is subject to high-quality control requirements. Instead the genome of an attenuated virus is inserted into human cells by means of a plasmid vector. Human cells that are harbouring the plasmid vector enable the
The approach of plasmid-based LAV vaccines exemplifies how the pace of innovation and converging technologies may blur current distinctions between a GMO and a non-GMO, and hence the legal status with regard the legislation on GMOs. Such rapidly evolving fields may also challenge a harmonized understanding of legal definitions across different countries. With respect to GMO regulation, it is not yet clear whether the status of plasmid-based live attenuated viruses will be based on a common interpretation among GMO national competent authorities.
\nA first element that will contribute to the interpretation can be sought in the GMO status of vaccines that are based on plasmid DNA derived from bacterial cells for use in humans or in animals, the so-called DNA vaccines [11]. Most of the EU member states do not regulate DNA vaccines as a GMO. The reasoning behind this is that a DNA vaccine is not considered an organism. Likewise, human cells transfected with plasmids should not be classified as GMOs, provided that the plasmid is not replicative and is unlikely to integrate into the cell genome. Taking into consideration Article 2 of Directives 2001/18 and 2009/41/EC, and corresponding annexes (Table 1), nucleic acid material (DNA or RNA) such as plasmids present under episomal form in a human cell is not considered as heritable material (of the human cell) unless the nucleic acid material is capable of continued propagation, for example, by integration of the nucleic acid material into the genome of the human cell, or when the plasmid contains an origin of eukaryotic replication. It should be noted that the probability of integration cannot be totally excluded for plasmids not known to contain integrative elements or homologous sequences. However, should an integration event occur, the risk for the human population or the environment, associated to the use of transfected human cells, would be negligible. Indeed, human cells can only propagate inside the human body or under controlled
A second element that prompts reflection on the GMO status, which is of particular relevance for the plasmid-based LAV technology, is associated to plasmids harbouring the full sequence of a virus. In that case the plasmid-transfected human cells may lead to the generation of replication-competent virus particles in the host human cells that eventually can be released into the environment. A plasmid harbouring a virus strain that has been genetically modified would be subjected to the GMO framework. However, the GMO status of plasmids harbouring the full sequence of a naturally occurring virus or attenuated virus has not been determined yet.
\nTherapeutic vaccines for cancer immunotherapy with chimeric antigen receptor (CAR) T cells are another medical development exploiting modern biotechnology tools. Cancer immunotherapy uses the patient’s own T cells that have been engineered to express a receptor targeting an antigen on the surface of tumour cells [12, 13, 14]. CAR T cell-based immunotherapy has shown remarkable efficacy against human malignancies, thereby providing a promising alternative to allogeneic haematopoietic stem cell transplantation which is known to be associated with severe side effects. It is anticipated that the number of developments using CAR T cells will continue to expand as current research now explores, for example, the potency of (CAR) T cells in solid tumours or the use of allogeneic ‘off-the-shelf’ T cells. The rapid pace of developments in part has been facilitated by the implementation of gene-editing tools to genetically modify human T cells.
\nGenome-editing techniques involving the use of site-directed nucleases (SDN), like the ribonucleoprotein-mediated gene editing of cells, make it possible to induce modifications in a predefined region of the genome without the need to introduce foreign (exogenous) DNA [15]. For some applications, the resulting organisms cannot be distinguished from those generated through classic mutagenesis or spontaneous mutations. While addressing how these techniques relate to the European GMO legislation and taking into account that organisms developed through classical mutagenesis are excluded from the EU regulatory framework for GMOs, a number of authorities or advisory bodies of EU members have expressed the opinion that applications of SDN, resulting in small point mutation or indels, could be exempted from the EU GMO regulation on the condition that the nuclease is not stably expressed from a recombinant nucleic acid molecule [16]. Therefore the advent of gene-editing techniques was challenging the boundaries of the GM regulation in the EU, at least until a legal opinion of the Court of Justice of the EU (ECJ) was issued. The ruling declared that organisms produced by mutagenesis techniques, including directed mutagenesis and applications of gene editing, should be regulated under EU GMO law, unless the mutagenesis technique has conventionally been used in a number of applications and has a long safety record [17]. Much opposition has been raised against this ruling, in particular with respect to the inclusion of gene-edited plants within the remit of GMO legislation [18, 19].
\nThe ruling applies to medicinal GMOs as well and will determine the legal status of CAR T cells obtained with gene-editing techniques with respect to GMO legislation. Apart from notifications in the context of CTAs, such an IMP would also require an ERA when reaching MAA (Regulation (EC) 726/2004). However, though human cells may survive in whole blood or synthetic media with a composition similar to human blood, these cells can only propagate inside the human body or under controlled
The continuous improvements in DNA synthesis technology also hold promise in the design of new vaccines. Developers may go further than recombinant DNA technology and make a step towards increased rational design, away from existing nucleotide sequences. For example, the genetic code of the virus can be redesigned so that 100% identity is preserved at the protein level with significant differences at the nucleotide level. This codon deoptimization has been described as an approach to generate attenuated viruses that can be used as vaccines [20, 21]. The synthesis of poliovirus (PV) as early as 2002 is considered as one of the first milestones in synthetic genomics [22]. Most recently, a clinical trial has been set-up involving two GMOs consisting of novel live attenuated polio vaccine candidates that have been developed through advanced DNA synthesis technology and codon deoptimization [23]. Though few preliminary questions were related to the GMO status of the novel live attenuated polio vaccines, it was merely the context of the global Polio Eradication Initiative and the associated efforts to minimize poliovirus facility-associated risks, as defined in the WHO’s Global Action Plan III (GAP III) [24] that added to the complexity of the legal procedure.
\nPoliovirus has a particular status from a global world health perspective since the launch of the global Polio Eradication Initiative in 1988. Immunization with trivalent live, attenuated oral poliovirus vaccine (OPV), composed of three strains OPV1, 2 and 3, has led to a drastic decline in the number of polio cases worldwide. However OPV is genetically unstable and can regain neurovirulence, leading to outbreaks of circulating vaccine-derived poliovirus (cVDPV). In a context of PV type 2 eradication worldwide and because the risk associated to the use of OPV2 was outweighing the benefits, it was decided to withdraw the type 2 component from OPV vaccination campaigns and to introduce the inactivated poliovirus vaccine, which is more expensive and relatively more cumbersome to administer. Nevertheless, due to its induced superior mucosal immunity, monovalent OPV2 is still used in responses to outbreaks of cVDPV2, thereby challenging the feasibility of eradication of PV2 [25]. It is within this context that a global consortium of investigators, governmental, non-governmental, academic and global health organizations worked on the development of two novel OPV2 vaccine candidates (nOPV2) with better genetic stability and reduced risk to regain a neurovirulent phenotype.
\nThe first-in-human (FIH) phase 1 study was conducted in Belgium. Although the clinical development of such novel vaccines was considered highly desirable from a world health perspective, the launch of a FIH study was considered under severe scrutiny in order to avoid any risk of introducing VDPV in a country declared polio-free for several years. As shedding of the nOPV2 was anticipated for a mean time of 2 weeks, the consortium decided to conduct the FIH phase 1 study with voluntary participants under full containment during 28 days, with strengthened containment measures. Rather unexpectedly, the study showed that ~50% of the subjects still were shedding after having left the full containment period of 28 days. Post-discharge biorisk management measures were applied to prevent the release of the candidate vaccines in the environment and to avoid contact with immune-compromised individuals.
\nThe WHO’s Polio Eradication Department encouraged further progress in the clinical study of the novel OPV vaccines and the consortium applied for a phase II CT with the nOPV2 vaccine candidates. On the basis of shedding and genetic stability data obtained with the FIH study, and the larger size of cohorts to be involved during the phase II study, the consortium applied for an authorization for deliberate release into the environment of the GMOs. In accordance with the Royal Decree transposing Directive 2001/18/EC into Belgian law, an ERA was submitted [26], a public consultation was organized, and a notification according to the provisions of Council Decision 2002/813/EC [27], the so-called summary notification information format (SNIF), was circulated. This enables an exchange of information between the EU member state and the Commission on the basis of relevant information.
\nIt has been the first example to our knowledge of EU member states commenting on the SNIF. One of the concerns raised by neighbouring countries was the transboundary release of the nOPV2, should the healthy volunteers not stay in Belgium during the period of virus shedding. Those concerns are not only related to GMO regulatory provisions but also to GAP III requirements, which describe a biorisk management system addressing areas associated with the design, operation and management for facilities handling poliovirus facilities [28]. It can be concluded that the regulatory pathway to the setup of the two first CT involving nOPV2 revealed an additional complexity involving increased exchanges both at national and international levels.
\nMedicines become more and more the result of different and converging technologies. For many human infectious diseases, no satisfactory vaccine is currently available, and the development of vaccines containing or consisting of GMOs is one of the innovative technologies implemented to meet some of the public health needs. Regulators involved in medicinal products for humans, as well as in GMOs, need to anticipate these developments, not only by enforcing safety regulations but also by ensuring the scientific review adheres to the principles of proportionality and case-by-case approach. From the applicants’ side, it is recognized that the regulatory pathway for novel technologies is complicated and not always straightforward. Early dialogue between applicants, risk assessors and the regulatory authorities is therefore paramount in addressing challenges with clinical translation of novel GMO vaccines.
\nThe steps that were undertaken towards the approval of early phases of a clinical trial investigating nOPV2 vaccine candidates in a post-OPV2-withdrawal era exemplify the importance of liaising among several regulatory agencies and public health institutions covering (international) public health objectives at national, European and global level. At the time the consortium that worked on the development of the nOPV2 vaccine candidates applied for its second clinical trial, it was still not clear whether the nOPV2 vaccine candidates were to be considered under the scope of GAP III. Because the consortium engaged as early as possible with advisory and/or regulatory institutions, the Belgian authorities were prompted to ask the WHO’s Containment Advisory Group to clarify the GAP III status of the nOPV2 vaccine candidates and, if these were to fall under the scope of GAP III, how to interpret or implement the GAP III guidelines in a phase II clinical study. The WHO’s Containment Advisory Group concluded that, according to the specific terms of usage proposed in the context of the protocol of the CT, the nOPV2 could be used outside the containment requirements of GAP III. It also requested the addition to the trial protocols of environmental monitoring for polioviruses around the trial sites, as well as monitoring of close and family contacts of trial subjects who continued to shed virus after the end of the trial period [29].
\nThis case exemplifies how different aspects of public health interrelate and contribute to the complexity of the regulatory maze to which applicants may be confronted when submitting clinical trial applications. Both the consortium and Belgian authorities liaised with several regulatory agencies and public health institutions covering different (international) public health objectives in order to ensure that risk management measures were proportional to the risk/safety assessment taking into account the intended use, the receiving environment and the likelihood of exposure.
\nA concern of developers that is acknowledged by the European Commission is the lack of harmonization of regulatory procedures of clinical trials with regard to the GMO legislative framework. The approval of clinical trials is within the remit of the member states and the interplay between the CT regulation and the GMO regulation might differ between the member states. This non-harmonized approach among member states, detailed under Section 2 of this chapter, is perceived as ineffective for the conduct of multinational clinical trials and as an impediment to the effective translation of research findings into clinical applications.
\nVery recently the first steps towards a common procedure for a subset of innovative therapies for human use involving the use of GMOs has been agreed upon among member states [30]. It concerns an application form specifically developed for clinical trials involving the use of human cells transduced with retroviral or lentiviral vector systems. Taking into account that the evaluation of clinical trial with respect to the GMO legislation will remain within the remit of national authorities, this initiative can be seen as a significant step towards enhanced communication among regulators. It is also of high value in light of the upcoming therapeutic strategies based on the genetic modification of T cells that target defined antigens presented by tumour cells and aids the patient’s own immune system to combat malignant diseases, the so-called CAR- and TCR-modified T cells.
\nThe European Commission continues to foster exchanges among member states with the aim of developing common application forms, increasing cooperation in the risk assessment of applications and identifying issues and questions with respect to the scope of the GMO regulatory framework.
\nAs already mentioned, at the time of planning a CT with a GMO in a European member state, the applicant may be confronted to a complex regulatory procedure, exceeding what is required for a standard study with an IMP. Alongside the standard Clinical Trial Application (CTA) and obtaining the advice from the ethics committee, questions regarding the GMO status of the IMP and the proper mandatory procedural steps may arise. In addition, should the IMP be identified as a GMO, the developer will need to identify a distinct competent authority in charge of reviewing the application according to the adequate procedural steps.
\nAs outlined earlier, the determination of the GMO procedural pathway for a CT in Belgium (meaning whether the CU only or both CU and DR procedures must be followed) is subject to a case-by-case examination taking into account the possible release of the GMO into the environment and the possible associated risks. To help the applicant, the competent authority for CTAs offers the possibility to request a scientific and technical advice (STA) prior to the CTA. The main objective of the STA is to facilitate the development of vaccines and therapeutic products by centralizing and analysing the applicant’s concerns at the time of starting the CT.
\nWithin the STA, the applicant is invited to request clarifications on the GMO status of the IMP, and on the GMO procedures to be followed, should it decide to proceed with the application. The competent authority for CTAs coordinates the contacts with experts, centralizes their responses and delivers a formal advice to the developer. As such, the STA is a means for developers to engage with the competent authorities and advisory bodies early in the process in order to (i) provide information that would facilitate further process and (ii) avoid possible misunderstandings with regard the GMO status and procedures, which consequently may save time for the developer.
\nWith novel technologies poised to result in the development of novel IMPs and the overall drive for sustained innovation, a number of regulatory hurdles can be identified, which developers face during the development of GMO vaccines. First, EU GMO Directives have been transposed into national legislations that include different regulatory specificities between member states. Second, new technologies may lead to the generation of organisms that are prone to different interpretations with regard to their (GMO) regulatory status, thereby hampering further harmonization of legislations. In addition, aspects such as the relevance of an ERA or detection and traceability requirements become in some cases disproportionate with respect to the actual risks that novel IMP represent for the general population and the environment. Overall, these aspects will increase the need of regulatory agencies and advisory bodies to anticipate the deployment of novel IMP, through continuous engagement with all stakeholders.
\nThe ECJ ruling has initiated the debate concerning the need to rewrite the GMO Directive 2001/18/EC, to have it more fit-for-purpose for the rapid pace of emerging technologies. This is particularly true for gene-editing technologies. Although it is primarily the impact on agri-food applications that has sparked these debates, the ECJ ruling will also have an effect on research and development activities and the development of a category of IMP. It is anticipated that the current debate on the appropriateness of the existing GMO regulatory framework may affect the future regulatory status of GMO medicines. This may have consequences through all stages of development, from R&D, through clinical translation and marketing authorization application.
\nAiming to overcome existing hurdles in the regulatory pathway, a number of initiatives have been taken in Belgium and among member states. Key challenges are being addressed, for example, with the STA at Belgian level, and tangible solutions have been formulated, such as the common form for CT with human cells genetically modified
New technologies in the field of biotechnology spark promising avenues for the development of novel biopharmaceuticals involving GMOs. Enhanced networking among all stakeholders should be further promoted in order to subject regulatory frameworks to critical review with the aim of keeping them up-to-date with upcoming developments and to support innovation while ensuring quality and safety for patients, the general population and the environment.
\nThe authors thank Aline Baldo, Didier Breyer, Fanny Coppens and Nicolas Willemarck (Sciensano) for critical reading. Figures 2 and 3 result from contributions from Nicolas Willemarck.
\nThe authors declare that they have no conflict of interest.
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