Classifications

• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N24/00—Investigating or analyzing materials by the use of nuclear magnetic resonance, electron paramagnetic resonance or other spin effects
  • G01N24/08—Investigating or analyzing materials by the use of nuclear magnetic resonance, electron paramagnetic resonance or other spin effects by using nuclear magnetic resonance
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01R—MEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES
  • G01R33/00—Arrangements or instruments for measuring magnetic variables
  • G01R33/20—Arrangements or instruments for measuring magnetic variables involving magnetic resonance
  • G01R33/28—Details of apparatus provided for in groups G01R33/44 - G01R33/64
  • G01R33/282—Means specially adapted for hyperpolarisation or for hyperpolarised contrast agents, e.g. for the generation of hyperpolarised gases using optical pumping cells, for storing hyperpolarised contrast agents or for the determination of the polarisation of a hyperpolarised contrast agent
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01R—MEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES
  • G01R33/00—Arrangements or instruments for measuring magnetic variables
  • G01R33/20—Arrangements or instruments for measuring magnetic variables involving magnetic resonance
  • G01R33/44—Arrangements or instruments for measuring magnetic variables involving magnetic resonance using nuclear magnetic resonance [NMR]
  • G01R33/46—NMR spectroscopy
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N24/00—Investigating or analyzing materials by the use of nuclear magnetic resonance, electron paramagnetic resonance or other spin effects
  • G01N24/006—Investigating or analyzing materials by the use of nuclear magnetic resonance, electron paramagnetic resonance or other spin effects using optical pumping
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01R—MEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES
  • G01R33/00—Arrangements or instruments for measuring magnetic variables
  • G01R33/20—Arrangements or instruments for measuring magnetic variables involving magnetic resonance
  • G01R33/28—Details of apparatus provided for in groups G01R33/44 - G01R33/64
  • G01R33/285—Invasive instruments, e.g. catheters or biopsy needles, specially adapted for tracking, guiding or visualization by NMR

Definitions

• the present invention relates to a sample analysis method based on nuclear magnetic resonance (NMR) spectroscopy.
• the invention also relates to a corresponding computer program product and device for carrying out the method.
• NMR nuclear magnetic resonance
• NMR magnetic nuclear resonance imaging
• IVMRI intra venous magnetic nuclear resonance imaging
• This company has developed a self contained "inside-out" miniature MRI probe in a tip of an intravascular catheter that allows for local high-resolution imaging of blood vessels without the need for external magnets or coils.
• This probe is shown in Figure 1.
• the advantages of this technique range from the very practical aspect of a low-cost system, since no expensive external setup is required, accessibility to the patient during the procedure, compatibility with existing interventional tools and finally resolution and diffusion contrast capabilities that are unattainable by conventional clinical MRI, due to the strong local gradients created by the probe and its proximity to the examined tissue.
• This intravascular probe serves as a first example for a wide range of applications for this method, which in the near future may revolutionize the field of clinical MRI.
• the medical applications for this technology include for instance detection and staging of prostate cancer, imaging tumors in the colon, lung and breast and intravascular imaging of the peripheral vasculature.
• Micro NMR coils are also known for a skilled man in the art. Developments of these "micro MRI” devices depend on the existence of high quality receiving coils. Microelectromechanical systems (MEMS) breakthroughs have made possible this new technology for the micro fabrication of Helmholtz micro coils for NMR spectroscopy. These Helmholtz micro coils demonstrate superior NMR performance in terms of spin excitation uniformity compared to planar micro coils. The improved spin excitation uniformity opens the way to advanced chemical analysis by using complex RF-pulse sequences. The fabricated Helmholtz coils have Q-factor greater than 20 due to electroplated coil turns and vias, which connect the lower and upper turns. For analyzing living cells, mechanical filters can be integrated for sample concentration and enhanced detection.
• MEMS Microelectromechanical systems
• NMR requires orienting a part of the nuclei magneton (spins) population along a chosen spatial direction.
• spins nuclei magneton
• the nuclei spins of a material can be locally oriented by radiating the sample with circularly polarized light. Methods using circularly polarized light are able to achieve high levels of polarization, up to 40%, under the right circumstances. Polarizations in this order of magnitude are considered hyperpolarized. Hyperpolarizability is obtained through the hyperfme spin-spin interaction electron-nucleus, the electron-photon spin exchange and the electronic-spin population saturation due to Fermi's exclusion principle applied to molecule's electrons.
• Hyperpolarized gases have found a steadily increasing range of applications in MRI and NMR. They can be considered as a new class of MR contrast agent or as a way of greatly enhancing the temporal resolution of the measurement of processes relevant to areas as diverse as materials science and biomedicine.
• the physics of producing hyperpolarization involves irradiating samples of Na with intense circularly polarized lasers of a wave length corresponding to one of the absorption bands for Na, followed by a "mechanical" polarization transfer to inert 129 Xe. The last is used as contrast agents in MRI and polarization transfer for other nuclear species for low- field imaging.
• the NMR effect can be observed and measured with optical methods. All Optical NMR hyperf ⁇ ne interactions allow for flip-flop spin scattering. This means that an electron can flip its spin by flipping simultaneously a nucleus into the other direction. This leads to a dynamic polarization of the nuclear spins. If the electron spin levels are saturated by a driving field, i.e. the population of the upper spin state is made equal to that of the lower state, such flip-flop processes try to re-establish thermal equilibrium, resulting in a nuclear spin polarization, which is described by a Boltzmann factor where the electron Zeeman splitting enters. Because the electron splitting is usually 1000 times larger than the nuclear splitting, the nuclei end up in an up to 1000 times enhanced polarization compared to their thermal equilibrium value - also known as an Overhauser effect.
• Yet another application of light angular momentum with magnetons is a high sensitivity- high frequency magnetometer. This solves one of the challenges raised by observing NMR effects, which is being able to measure the transient response of the magnetic fields produced by spinning nuclei.
• a magnetometer has been demonstrated operating by detecting optical rotation due to the precession of an aligned ground state in the presence of a small oscillating magnetic field. The projected sensitivity is around 20pG/pHz (RMS).
• the Micro NMR is an appealing chemical analysis device for being included in an ePill device or in an inexpensive non-invasive blood analysis apparatus. It shall consume low power, be confined within a small volume and shall not include any paramagnetic materials (FDA). "TopSpin Medical" micro NMR or other "fixed magnet based” NMR are not suitable for the purpose, since these include a permanent magnet, require long acquisition time and hence consume power.
• An ePill is a small electronic device that is swallowed by a patient for performing an analysis of internal organs of the patient.
• Photon-electron spin interaction has been extensively observed and modeled and it is the basis of the optical pumping technology for hyperpolarizability of gases. Unfortunately, this technique is not capable for producing fluid hyperpolarizability, due to thermal molecular movement and interactions.
• Photon OAM interactions with nuclei has been recently analyzed as a method of controlling the spin-spin interaction within nuclei. It uses energetic X rays, not desirable for "in-vivo" applications. Furthermore, by applying a constant magnetic field to a sample containing N nuclei, at room temperature, one can calculate the maximum number of oriented nuclei (Boltzmann distribution), which is around 10 "5 N. In order to extract a significant magnetic signal from the sample, one has to implement high quality factor coils or enlarge the size of the sample. In both cases the volume occupied by the receiver shall increase, which makes the permanent magnet micro NMR difficult to integrate within an ePill. Thus, the object of the present invention is to provide an improved method and apparatus for a sample analysis based on NMR spectroscopy.
• a method of analyzing a sample consisting of molecules the analysis being based upon nuclear magnetic resonance spectroscopy, the method comprising the following steps:
• the obtained free induction decay (FID) signal is much stronger than the corresponding signal obtained by using traditional NMR spectroscopy methods.
• the sensitivity of the measurement technique is greatly improved.
• the obtained FID signal is also less noisy and better resolution can be achieved. As a consequence smaller samples can be analyzed.
• a computer program product comprising instructions for implementing the method according the first aspect of the invention when loaded and run on computer means of an analysis device.
• a device for analyzing a sample consisting of molecules the analysis being based upon nuclear magnetic resonance spectroscopy, the device comprises: a light source; - means for introducing orbital angular momentum into the light; a recipient for accommodating the sample;
• FIG. 2 is a graph showing a potential vector/as a function of a radial coordinate p;
• Figure 3 is a graph showing the potential vector/ as a function of the radial coordinate p by using other parameters as those used for Figure 2;
• FIG. 4 shows possible OAM-molecule interactions
• FIG. 5 is a block diagram of a laboratory setup for carrying out fluid analysis in accordance with an embodiment of the present invention
• FIG. 6 shows a computer generated phase hologram displayed on a spatial light modulator panel
• FIG. 7 shows a hologram projection on a screen placed three meters apart from the spatial light modulator
• FIG. 8 shows a projection of selected Laguerre Gaussian diffracted orders after spatial filtering
• FIG. 9 shows the chemical structure of the sample used in an exemplary embodiment for which a free induction decay (FID) signal can be obtained;
• FIG. 10 shows the used light pulse drawn along a time line and the obtained digital
• FIG. 11 is a flow chart depicting a method of performing a high resolution fluid analysis in accordance with an embodiment of the present invention
• - Figure 12 shows a spectrum of a free induction decay signal
• - Figure 13 is a block diagram of another setup for carrying out the sample analysis in accordance with another embodiment of the present invention.
• the present invention is based on the fact that the OAM of absorbed photons is transferred to interacting molecules (angular momentum conservation) and as a consequence:
• Electron state reaches a saturated spin state; - Angular momentum of the molecule (around centre of mass of the molecule) is increased and oriented along the propagation axis of incident light; and
• All magnetic magnetons precession movement associated with the molecules are oriented along the propagation axis of incident light.
• the above make possible to obtain hyperpolarizability of fluids by illuminating them with light carrying OAM and possibly spin, i.e. angular momentum, and implement an NMR device without a permanent magnet.
• the quantum electrodynamics (QED) framework can be considered as a starting point for explaining the interaction of photons with OAM with matter. This has been applied for a hydrogenic model, and it has been found out that the OAM part of the incident light induces a rotation of the molecule, of a momentum equal to the light's momentum. This finding has been confirmed by stating from a more general Bessel model of light with OAM.
• the spontaneous or stimulated emission of photons endowed with OAM is a phenomenon not yet understood, modeled or experimentally proven. Therefore, the generation of beams with OAM is accomplished through optical means of spatial phase change, interference and diffraction of Gaussian beams.
• Four methods (five if the two methods using cylindrical lenses are considered separate methods) are available as summarized in Table 1.
• the power conversion efficiency is the ratio of the output power (beam with OAM) to the power of the input beam.
• the highest OAM number obtained in a laboratory is as high as 10000 ⁇ L per photon. This is obtained by an elliptical Gaussian beam focused by a cylindrical lens.
• Table 1 Methods for generating light with OAM.
• the holograms are
• the sample nuclear magnetic momenta are oriented (precession movement) along a selected spatial direction. This is usually achieved with a strong magnetic field or - within more recent applications - with polarized light.
• the parameters in a nuclear magnetic resonance (NMR) FID signal contain information that is useful in biological and biomedical applications and research.
• the optical pump can achieve about
• the main concept of the present invention refers to a new method to orient the nuclei of a sample along a selected spatial direction using the interaction of light with OAM with molecules. The following sections focus on the theoretical explanation of this interaction and an experimental proof of the concept. Following notations and symbols are used throughout the remaining description:
• A(f,t) A pol u(r)e l( " S - ⁇ ' ] (1 :3)
• V — I n + L + — 1 (I AD dp p p 3 ⁇ ⁇ dz z ⁇ l ⁇ Z)
• the ratio s ⁇ , p V ⁇ ) is time independent. It is also linear with /, therefore the electromagnetic energy flow about the beam propagation axis increases proportional to /. The rotational energy transferred to molecules interacting with light is increased with /. This holds ⁇ 7 ( — * ⁇ if ⁇ /w 0 is kept constant for different /'s. The magnitude of s ⁇ , p ⁇ r ⁇ ) reaches higher values for small W 0 , which makes the observation of the mentioned dependence easier for tightly focused beams.
• the molecule interacts with a light beam propagating along Oz axis, with energy h(O , linear momentum tik and orbital angular momentum of fi I.
• the reference frame origin is chosen at the beam waist of the light beam, as described above.
• the ⁇ index marks the time independent Hamiltonian, while the ⁇ index represents the light-molecule interaction Hamiltonian (perturbation).
• the first order perturbation theory gives:
• H 1 J is the time independent operator associated to the perturbed Hamiltonian. From (3:9) and (3:15) one can find the value of the transition probability as: h.c. is the complex harmonic conjugate of the transition matrix:
• Photon absorption occurs when the final energy of the molecule exceeds the initial value ( C0 6 ⁇ ⁇ 0 ). This condition nulls the h.c. term.
• the transition probability for absorption is proportional to:
• the matrix element is expressed for every particle involved in the photon absorption process, and the absolute value of their sum is calculated.
• the matrix element for particle n (first order perturbation theory) is:
• the matrix element is a sum of 4 terms:
• M n J f( _ t l p describes the kinetic energy contribution of a particle.
• the probability of OAM interaction with molecules is zero at spatial points placed far from the centre of the light beam or in the centre of the light beam.
• M 11 -i ⁇ (/I 9//,, (P,, ) i(kz ⁇ -B n )
• the matrix element is:
• the third term is:
• the matrix element M' represents the interaction of the OAM with electron (and nucleon) spin.
• the fourth term is of a major interest, since it depicts a linear dependence of a transition probability on a parameter of the incident light, other than frequency or spin:
• transition matrix coefficients - ⁇ n and M n f ⁇ ⁇ l p include terms proportional
• the maximum value of the transition matrix coefficients ⁇ n f ⁇ _ l l p and ⁇ - n j ⁇ , ⁇ , P is obtained with a light beam with the radius as close as possible to the Airy disk radius.
• Atoms and molecules may contain different types of angular momenta.
• the most important reservoirs include orbital angular momentum of electrons, rotational motion of molecules and spin angular momentum of electrons and nuclei. Not all these types of angular momenta couple directly to the radiation field: in free atoms, only the orbital angular momentum of the electrons is directly coupled to the optical transitions.
• the different types of angular momenta are in general coupled to each other by various interactions which allow the polarization to flow from the photon spin reservoir through the electron orbital to all the other reservoirs, as shown schematically in Figure 4.
• Transparent molecules These are cases of “quasi-transitions", where photons interact with orbitals, but do not have enough energy to produce an excited molecular state. The photon is absorbed and emitted by the molecule almost at the same time (short "quasi-state” life time). There are changes within the incident and emitted photons momenta and energies (e.g. Raman back scattering). Therefore, light with OAM will interact with transparent molecules as well, transferring the photon angular momenta to the rotational momentum of the molecule.
• the optical pumping shows that molecules can be hyperpolarized with light carrying spin (circular polarized light).
• the method has been successfully used for obtaining hyperpolarized gases, with applications in MRI.
• the present invention adds the photons an OAM, therefore increases the orientation of the molecular momenta along the direction of propagation of the light and increases the probability of obtaining hyperpolarized molecules within fluids. Hence, an NMR analysis of the fluid is possible.
• FIG. 5 shows an exemplary setup for analyzing fluids in accordance with the teachings of the present invention.
• the white light is produced with an HP Mercury, IOOW white light source 501, and is collimated so that the diameter of the beam is roughly lmm.
• the collimated light i.e. the beam, is then sent to a beam expander (1 :20) 503.
• a mechanical shutter 505 in this case a rotating wheel, which is capable of generating an electrical signal synchronized to the opening of the shutter.
• a manual shutter 507 while the mechanical shutter 505 is operational.
• This shutter blocks the light while measurements are performed in “dark” states, while the entire system operates as in “light” conditions, and it is required for maintaining the same noise environment for all measured states.
• the light After passing through the beam expander 503, the light is circularly polarized with a linear polarizer 509 followed by a quarter wave plate 511.
• a space light modulator (SLM) 513 in this case a liquid crystal on silicon (LCoS) panel, 1280x720, 20> ⁇ 20 ⁇ m 2 , 45TN LC effect, l ⁇ m cell gap produces a computer generated phase hologram designed to change the Gaussian incident beam to a Laguerre Gaussian (LG) beam, carrying OAM and spin.
• the value / of the OAM is a parameter of the hologram and can be increased to values up to 40, but cannot be easily further increased due to practical issues related to spatial filtering.
• the zero th order diffraction spot conserves its position, whereas its adjacent LG diffracted beams obey the normal diffraction grating dispersions laws.
• the same hologram produces LG beams carrying OAM of ⁇ 1, Ml+ 1), ⁇ (l+2)... ⁇ for different wavelengths.
• a screen i.e. spatial filter 517, was used to block the zero th order and the diffracted LG beams were selected that carry OAM and spin. The result is shown in Figure 8.
• the dispersed diffracted LG beams are collected and focused onto the sample by use of a concave mirror 519 and a fast microscope objective 521.
• the highy# is required in order to satisfy the condition of a beam waist as close as possible to the Airy disk size.
• a voltage proportional to the voltage at the coil terminals, therefore proportional to the magnetic flux variation through the coil is recorded by a measurement device, in this case a Tektronix TDK 700 series scope, on a 5mV input scale range, 25MHz sampling frequency, 20MHz input low pass filter (LPF), resolution of 16 bits (high resolution), real time acquisition, 200K samples.
• a measurement device in this case a Tektronix TDK 700 series scope, on a 5mV input scale range, 25MHz sampling frequency, 20MHz input low pass filter (LPF), resolution of 16 bits (high resolution), real time acquisition, 200K samples.
• an electromagnetic magnet 526 for creating a magnetic field around the sample. This magnet is used for directing the light beam so that the nuclear magnetic polarizability induced in the sample can be changed. A static magnetic field can thus be applied to the sample such that the orientation of the B field is perpendicular to the OAM light beam's direction of propagation.
• the magnetic field helps to create an organized FID when the OAM light is switched off as shown in Figure 10. From this figure it can be seen that once the light is turned off, the resulting FID signal is then sampled using an analog to digital converter (ADC).
• ADC analog to digital converter
• the trigger event has been provided by the synchronization output of the mechanical shutter 505.
• the photo diode pin device
• the photo detector 529 in Figure 5 has been used as a trigger signal delay estimation device. It measures the delay between the synchronization signal generated by the mechanical shutter 505 and the raise time of the light passing thorough the sample. This value is measured once and used as the trigger delay value for the rest of the measurements.
• the acquired data set is passed to a fast Fourier transformer (FFT) 531 which performs the FFT algorithm (Hamming window, -35dB phase rejection, and average factor of 20), which produces the amplitude for the frequency domain of the free induction decay (FID) signal.
• FFT fast Fourier transformer
• controller unit 533 which can be a personal computer (PC) for processing the obtained FID signal.
• the controller unit 533 may be connected to a driver board 535, which controls the operation of the SLM unit 513.
• the data acquisition setup summary is given in Table 2.
• the acquisition time and number of samples shall be improved in experiments seeking the determination of chemical species present within the fluid sample.
• the setup described above allows the acquisition of the magnetic FID of a sample illuminated with light with spin and an OAM of 10/z and comparing it with the same FID coming from the not illuminated sample. The last case might seem unnecessary, since the
• step 1101 the light source 501 is turned on.
• step 1103 the light acquires OAM and possibly spin once it passes through the polarizer 509, quarter wave plate 511 and SLM apparatus 513.
• step 1105 the light is dispersed and in step 1107 the light is filtered with a specified polarization and OAM.
• step 1105 is only needed, if OAM is generated by methods that have as a second order effect the light dispersion. Dispersion occurs only when the OAM is generated with diffracting gratings. If the dispersion is generated then it needs to be further filtered for obtaining the first order diffracted beam. In this case the dispersion is done by the SLM unit 513. The filtering is done by using the aperture 517.
• the light beam is focused onto the sample by using the concave mirror 519 and microscope objective 521.
• molecule orbitals electron spins
• angular momenta and nuclei will get oriented (Larmor precession movement) around the light beam propagation axis.
• This process shall produce a detectable FID signal, which shall reflect in peaks in the FID spectrum for the positive edge triggered acquisition, positive edge corresponding to the event "light start passing through the sample”.
• the coil 525 submerged in the fluid serves as an FID detector.
• the coil symmetry axis overlaps the beam propagation direction, while the center of the coil 525 is positioned on the virtual focal point of the objective.
• step 1111 the light is sequentially switched on and off for obtaining (step 1115) the FID signal.
• step 1113 a sequence of magnetic fields is created by the coils 526. These magnetic fields are perpendicular to the direction of the light. When the light is turned off, the magnetic field is created and the thermal nuclei shall relax their orientation, and will get oriented to be more or less aligned with the magnetic field. Thus, the nuclei get oriented into two directions, the first direction being determined by the direction of the light and the second direction being determined by the direction of the magnetic field.
• the pulse period is about 70ms and the duty factor is 50%.
• the applied magnetic field can be a static field or it can be an RF field that is tuned to interact more strongly with specific nuclei. Alternatively this can be done by applying another light beam perpendicular to the first beam.
• FID excitation sequences a more efficient method to produce white light and means to modify the light spectrum that is sent to the sample, a more efficient way to modulate the
• OAM OAM and a better data acquisition (longer acquisition sequences, higher data rates at higher sensitivities) system.
• Figure 12 shows a portion of the spectrum obtained from the FID with the acquisition triggered by the negative light edge as shown in Figure 10 after having carried out the frequency domain transformation by the FFT unit 531.
• all of these FIDs were collected in the presence of a perpendicular magnetic B field equal to approximately 0.1 Tesla.
• Figure 13 shows a slightly modified configuration of the configuration of Figure 5.
• the apparatus shown in Figure 13 is equally arranged for performing a high resolution sample analysis based on NMR spectroscopy.
• the SLM 513 is replaced with a holographic plate 1303 for producing the desired type of light endowed with spin and OAM.
• the LNA 527, photo detector 529, FFT transformation unit 531, controller 533 and driver board 535 are not shown in Figure 11, but their functioning is integrated into the NMR specific signal processor 1305.
• the invention is applicable in all situations where an NMR chemical sample analysis is required.
• it can be used for "in-vivo" applications, e.g. in ePills, intelligent catheters, etc.
• the embodiments of the invention do not contain any magnetic materials for obtaining hyperpolarized fluid; therefore it is suitable for "in-vivo" operations.
• the invention equally relates to a computer program product that is able to implement any of the method steps of the embodiments of the invention when loaded and run on computer means of the devices mentioned above.
• a computer program may be stored/distributed on a suitable medium supplied together with or as a part of other hardware, but may also be distributed in other forms, such as via the Internet or other wired or wireless telecommunication systems.
• the present invention equally relates to an integrated circuit that is arranged to perform any of the method steps in accordance with the embodiments of the invention.

Landscapes

• Physics & Mathematics (AREA)
• General Physics & Mathematics (AREA)
• High Energy & Nuclear Physics (AREA)
• Condensed Matter Physics & Semiconductors (AREA)
• Analytical Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Spectroscopy & Molecular Physics (AREA)
• Biochemistry (AREA)
• General Health & Medical Sciences (AREA)
• Immunology (AREA)
• Pathology (AREA)
• Magnetic Resonance Imaging Apparatus (AREA)
• Investigating Or Analysing Materials By Optical Means (AREA)
• Investigating, Analyzing Materials By Fluorescence Or Luminescence (AREA)

Applications Claiming Priority (2)

Publications (1)

Family

ID=40566282

Family Applications (1)

Country Status (4)

Families Citing this family (15)

Family Cites Families (6)

• 2009
  • 2009-01-15 WO PCT/IB2009/050145 patent/WO2009090610A1/en active Application Filing
  • 2009-01-15 EP EP09702507A patent/EP2235510A1/en not_active Withdrawn
  • 2009-01-15 CN CN200980102460.2A patent/CN101939638B/zh not_active Expired - Fee Related
  • 2009-01-15 JP JP2010542719A patent/JP5264933B2/ja not_active Expired - Fee Related

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events