The invention concerns the field of diffuse optical imaging applied to the medical sphere and notably in vivo and ex vivo fluorescence imaging.
These techniques can be used to implement non-invasive diagnosis systems through the use of non-ionizing radiation, which are easy to use and low cost.
One application of diffuse optical imaging is fluorescence imaging, in which a fluorescent marker or fluorophore (chemical substance of a molecule capable of emitting fluorescent light after excitation) is injected into a subject to be examined and fixes itself to certain specific molecules e.g. cancerous tumours. The region of interest is illuminated at the optimal excitation wavelength of the fluorophore. A fluorescence signal is then detected.
A diffuse optical imaging technique also exists without the injection of a fluorescent marker. In this case, it is sought to analyze a signal at the same wavelength as the excitation wavelength.
One example of a device for implementing one of these fluorescence tomography techniques is illustrated
An excitation laser 8, e.g. in titanium sapphire, delivers a pulse train at a certain repeat rate, for example 80 Mhz, with a mean power of a few hundred milliwatts output from the excitation fibre 10. This laser can be wavelength tuned to excite different types of fluorophores. The laser, injected into the excitation optical fibre 10, allows probing of the sample 11, a diffusing medium in which a fluorescent marker is or is not included depending on the type of technique used.
If a fluorescent marker is present in the medium, the fluorescence it emits is collected by a second—detection—optical fibre 12 and the filtered fluorescence signal (reference 16 designates a filter) is measured using a detector e.g. a photomultiplier tube 4 connected to means 13 allowing the fluorescence signal to be measured.
If there is no fluorescent marker, then the examination is a diffuse optical examination, and it is the diffused signal which is collected by the second optical fibre 12, the filter 16 then being adapted to the excitation wavelength.
Whatever the technique used, to achieve better sensitivity there is a possible temptation to inject high laser energy into the examined medium. However a problem of damage to this medium arises above a certain energy density. This is notably the case when working on a tissue and notably on a living tissue e.g. a tissue of a human organ (breast, prostate, brain, testicles, arms, carotid, thyroid . . . )
It is possible to endeavour to widen the pulse geometrically. However, in addition to the fact that the tissues will evacuate heat less easily, the resolution of the image will be deteriorated on and after a fibre 10 diameter of the order of 1 mm.
Another problem is the problem of sensitivity: it is desired to achieve the best collection of the photons emanated by the examined medium 11. It is effectively sought to minimize losses, notably at the interfaces.
Another problem relates to edge effects which hamper reconstruction, these being difficult to model accurately. It is therefore ascertained that the boundaries of the medium are a source of error when reconstructing the properties of the medium.
The invention first concerns a coupling device to couple at least one optical fibre with a view to optical examination of a medium to be examined, the examination being of diffuse optical imaging type, comprising:
In the remainder hereof, the expressions matrix or mass or diffusing matrix or diffusing mass are used indifferently.
When in use, the matrix is placed in contact with the sample or examined organ.
Said device may comprise:
More generally, any number of housings and/or fibre ends can be provided in the same matrix, the housing(s) being intended to receive one or more fibres (excitation and/or collection fibres).
In particular a signal collecting fibre, whether a fluorescence or diffusion signal, can be inserted permanently or in a housing inside the diffusing matter of the mass or matrix. In this case, improved efficacy of signal collection is ascertained compared with the case in which this fibre is located outside the coupling device of the invention.
The effect of using a matrix is to distance the boundary of the medium from the ends of the excitation fibre(s) and/or collection fibre(s), which limits the perturbation related to edge effects. With a thick matrix, whose thickness (along a direction substantially perpendicular to the bearing surface) exceeds a few cm, e.g. greater than 3 cm or 5 cm, the influence of the edges becomes negligible; the conditions are then close to those of an infinite medium which subsequently facilitates and improves the reconstruction of the optical properties of the medium.
Preferably:
Therefore, it is possible to position the end of one or more excitation fibres further from the interface with the examined medium than the end of one or more collection fibres, to maximize the collected energy. According to one preferred embodiment, the height h is chosen to be zero for at least one collection fibre, so that at least one collection fibre is in contact with the medium, or as close as possible thereto, to maximize the collected energy.
If a fibre, which transmits an excitation or incident signal, is inserted in a housing of the matrix or the mass in diffusing material, or if its end is contained permanently in this mass, said mass diffuses the excitation radiation. This diffusion is similar to that of the examined medium, if the diffusing medium has optical properties close to those of the examined medium. By close is meant a relative deviation of less 30%, preferably 20%, for at least one of the parameters under consideration: absorption coefficient or reduced diffusion coefficient.
In this case, the interface and the medium examined can be considered as a single diffusing medium. Additionally, this simplifies calculations during the reconstruction step.
Preferably, the diffusing medium therefore has absorption and reduced diffusion coefficients μa and μs′ close to those of the tissues of the examined medium.
The diffusing material, for example, therefore has a reduced diffusion coefficient μs, greater than 0.1 cm−1 and less than 700 cm−1, and preferably between 1 and 50 cm−1, and further preferably between 5 and 20 cm−1
It may have an absorption coefficient μa greater than 0.01 cm−1 and less than 10 cm−1. Preferably, this coefficient is lower than the reduced diffusion coefficient μs′. Preference is given to values of between 0.01 cm−1 and 1 cm−1.
An absorbent layer may cover the mass in diffusing material, in part or at least in part. This may be a layer of black paint or of anodized metal partly covering or at least partly covering the matrix. Preferably, the contact surface with the medium is free of this layer.
The spot of the excitation beam, on the bearing surface intended to be in contact with the object to be examined, preferably has a surface area St of between 1 mm2 and 1 cm2 or a few cm2, for example 5 cm2, or of the order of about ten cm2 or a few tens of cm2, for example lying between 10 cm2 and 20 cm2 or 50 cm2.
According to another particular embodiment of the invention, the bearing surface further comprises one or more protuberances of substantially rounded shape with no sharp edges, extending the bearing surface that is to be applied against the object to be examined.
Said device may advantageously comprise at least one housing, or the end of at least one fibre, whose bottom is located substantially in or at said protuberance.
According to the invention, the excitation or incident beam is brought from a source, generally a point source located outside or inside the diffusing mass, but the tissue is broadly illuminated due to the diffusion of the excitation signal in the diffusing mass.
The source or the source point may have a diameter of less than 3 mm, preferably less than 500 μm, whilst the tissue is illuminated by a spot with a diameter of at least 1 mm or 5 mm or 10 mm, preferably less than 20 mm or than 5 cm. This point source may be located in the matrix, this case notably corresponding to an optical fibre of which one end is included in the diffusing mass, this end then possibly being likened to the point source. This is particularly the case when the excitation fibre has its end inserted in an opening provided in the diffusing mass, or the case in which the excitation fibre has its end fixed permanently in the diffusing mass e.g. by moulding. However, the light source in some cases may be located at a distance away from the diffusing mass.
An end portion of one of the fibres may only comprise a core if the matrix acts as cladding.
A further subject of the invention is a diffuse optical imaging device, notably for fluorescence imaging of a medium, comprising:
a) means e.g. a laser forming a radiation source to form incident radiation on the medium, at least at a first wavelength,
b) a coupling device according to the invention, comprising an optical fibre of which one end is arranged permanently in the diffusing mass, or comprising an optical fibre arranged in the housing provided in the mass of diffusing material,
c) detection means to detect a diffused or fluorescence signal, derived from the medium being examined.
This optical fibre of the coupling device may be a collection optical fibre to collect a signal emanated by a medium, and to convey it towards the detection means.
Said device may further comprise an excitation optical fibre to bring the incident radiation onto to the medium to be examined.
The optical fibre, or an optical fibre, of the coupling device may be an excitation optical fibre to bring the incident radiation onto the medium to be examined.
One particular embodiment is also a case in which an excitation light source, such as a laser or optical fibre, is positioned at a distance from the diffusing matrix and the corresponding radiation is sent towards the medium to be examined by passing through the matrix, one or more collection fibres being positioned in a matrix according to the invention, either permanently or temporarily.
One particular embodiment is also the case in which an excitation light source, such as a laser or optical fibre, is located at a distance from the diffusing matrix and the corresponding light radiation is sent towards the medium to be examined without passing through the matrix, one or more collection fibres being positioned in a matrix according to the invention, permanently or temporarily.
The radiation source may be a pulsed, continuous-time or amplitude-modulated source. The diffuse optical imaging technique applied may be of time-resolved type, or any other type. This technique can be applied to fluorescence diffuse optical imaging e.g. fluorescence tomography, or to the determination of the optical properties of diffusing media.
A further subject of the invention is an examination method of diffuse optical imaging type, to examine part of a medium, in which at least one coupling device of the invention is used and wherein:
Preferably, a fluid is applied between the bearing surface of the diffusing medium of the coupling device and the surface of the medium to be examined.
With or without coupling fluid it was able to be ascertained, unexpectedly, that if the medium to be examined has certain flexibility, for example as with living tissues, the exertion of a pressure on the coupling device positioned against the medium to be examined makes it is possible to increase the reception signal. When implementing a device according to invention, comprising at least one excitation fibre and/or at least one collection fibre, pressure may then advantageously be applied to place the coupling device against the examined medium, so as to cause a fluid contained in this medium to flow outside part of this medium towards a region located on the periphery of the coupling device.
A first example of an embodiment of the invention is given
This figure illustrates the fibres 10, 12 which respectively bring an excitation beam 9 (or more generally an incident beam) into a diffusing medium to be examined 11, and collect a fluorescent or diffusion signal emanated by this same medium.
In this example, the ends of the two fibres 10, 12 are inserted in an interface element 20 in diffusing material. In the remainder hereof the expression <<matrix>> will be used, but either of the terms <<interface>> or <<mass>> may be used indifferently in its stead. This matrix may be in a solid material, but it can also be in a soft, viscous or liquid material, in which case it is intralipid for example.
The matrix here is of substantially cylindrical shape, having two faces 22, 24 perpendicular to the axis XX′ of revolution of the cylinder. One of these faces (face 24 in
Each closed end 271, 291 is also the part of the housing 27, 29 closest to this surface 22. Via the end 271, the excitation beam 9 leaves the excitation fibre 10 and enters the matrix; via the end 291 the diffusion beam 9 leaves the matrix and is collected by the collection fibre 12. Each cavity thus defined in the matrix is adapted to receive at least one fibre. The diameter of each opening 26, 28 is therefore substantially the diameter of the fibre or fibres it is intended to receive. A coupling liquid can be placed at the bottom of either one and/or both of the cavities; the refractive index of this liquid is preferably close to that of the matrix material.
Advantageously, to improve the optical coupling between the matrix and the medium 11 being examined, and hence to facilitate modelling of the propagation of light rays in the diffusing system consisting of the matrix and medium 11, the optical properties of diffusion and optionally of absorption of the matrix material can be chosen to be close to those of the medium to be examined.
Therefore the reduced diffusion coefficient μ′s of the constituent material of the matrix may be greater than 0.1 cm−1 and is preferably between 1 cm−1 and 700 cm−1, more preferably between 1 and 50 cm−1, and further preferably between 5 and 20 cm−1, these values being well adapted to excitation or fluorescence wavelengths in the red or infrared.
The absorption coefficient μa of the matrix constituent material may vary between 0 cm−1 and 10 cm−1 and preferably between 0.01 cm−1 and 1 cm−1 which, again, are well adapted to excitation or fluorescence wavelengths in the red or infrared.
With a low absorption coefficient μa it is possible to prevent too much signal loss and excessive heating of the matrix (any absorption leads to a rise in temperature). Preferably a matrix 20 is formed having the same absorption coefficient μa as the examined matter 11 in order to form the most homogeneous medium possible, with a view to reducing the influence of the interface and facilitating reconstruction. Therefore, in some cases, a low absorption coefficient will be chosen, whilst in other applications an absorption coefficient will be preferred that is close to that of the medium under consideration.
A composition of titanium dioxide ink resin type is a suitable material. It is also possible to use a diffusing polymer or a transparent polymer to which diffusing particles are added, or cryogel. Cryogel is a polyvinyl alcohol compound often abbreviated to PVA whose consistency can be more made more or less viscous and even solid, by subjecting it to freeze-defreeze cycles. As a variant, it is also possible to use viscous or solid materials containing agarose gel or animal gelatine. Preferably the refractive index of the material is chosen to be close to that of the medium examined.
The excitation radiation 9 used may notably be in the infrared, for example having a wavelength or wavelengths of between 400 nm and 1300 nm, preferably between 600 nm and 950 nm. The collected signal 15 either has a wavelength that is greater than the wavelength or wavelengths of the excitation beam (for a fluorescence signal derived from an exogenous marker) or a wavelength substantially identical or close to the wavelength(s) of the excitation beam (as with a diffusion signal).
The surface 22, or a bearing face, allows the device to be applied against the surface 11′ of the medium 11 to be examined. In general, this surface 22 is planar, enabling it to be applied against a surface which itself is at least partly planar.
However, it may also be curved or contain a curve; it will be seen below that other surfaces are suitable, in particular for the examination of soft or flexible tissues, with protuberances having rounded shapes or with at least one non-zero radius of curvature in a plane perpendicular to the surface of the medium to be examined.
The matrix 20 may be of cylindrical shape as in
Irrespective of the envisaged embodiment, the solid matrix has an outer surface 20′, 30′, 40′, 50′ which, during use, is intended not to be in contact with the surface of the examined medium. This surface can be partly coated with an absorbent layer 31, 41, 51 formed for example of a layer of dark paint, or a layer in anodized metal, but not in the opening regions 26, 28 which allow the fibre or fibres 10, 12 to be positioned in the matrix, and not on the surface 22 to be placed in contact with the medium to be analyzed.
In general, if an excitation fibre 10 is inserted in a coupling device according to the invention, the source appears as a point in the diffusing medium of the matrix. However, there is a diffusion effect of the excitation radiation in this matrix, before it reaches the surface 11′ of the examined medium 11. For example,
The impact of the incident beam on this medium is therefore not a point impact but distributed over a wider surface than if the fibre were used alone without the coupling device of the invention. The surface density of a signal is therefore lower than when excitation is directed with the same excitation signal intensity towards the medium to be examined without the device according to the invention.
Damage to the medium to be examined is therefore minimized and even avoided. However, the source is considered as remaining a point source and the laser beam or optical fibre can be modelled as being point sources. The diffusing matrix may also be taken into account in the model used for reconstruction, the diffusing medium incorporating the diffusing matrix.
Preferably, the depth of each housing 27, 29 is adapted to the function of the fibre it is to receive.
In particular, it is effectively preferable that the distance between the end of the excitation fibre 10 and the surface 11′ of the matter to be analyzed should be longer than the mean free pathway of isotropic diffusion, the latter being the inverse of the coefficient of reduced diffusion (=1/μs′) of the excitation photons in the diffusing medium.
Also, it was ascertained that it is preferable that the collection fibre should lie further ahead in the matrix than the excitation fibre, and therefore its end should lie fairly close to and preferably in contact with the surface 22
In general, irrespective of the embodiment, the surface 22 intended to be contact with the region which delimits the diffusing medium is preferably nearer the closed end 291 of the cavity 29 intended to receive the signal collection fibre 12, than the closed end 271 of the cavity 27 intended to receive the excitation fibre 10. In other words, the height H which separates the surface 22 from the end 271 of the cavity 27, which end is the closest to this same surface, is greater than the height h which separates this surface 22 from the end 291 of the cavity 29 the closest to the surface 22. For example, H lies between 0 and 5 cm, preferably between 1 mm and 10 mm, whilst h lies between 0 and 5 cm, preferably between 0 and 5 mm, and is more preferably close to 0.
The efficacy of signal collection is increased when the end of the collection fibre 12 is close to the interface 22. Some photons derived from the examined medium and effectively following the pathway referenced 51, 52, 54 (shown
Again preferably, the spot 37 of the excitation beam, such as illustrated
By denoting s the surface of the end of the fibre and S the surface 22 of the diffusing matrix 20, the maximum authorized energy to be taken into account will be lower the greater the value of S, and the spatial resolution of reconstruction will notably depend on s.
In the above examples, the matrix comprises two openings and two housings, one for each of the fibres 10, 12.
As a variant, it is also possible to use a matrix for each fibre, as in
As a further variant, it is also possible to use one matrix for several fibres, as in
Here again, the depth of each housing is preferably adapted to the type of fibre to be received.
It is also possible (
However, the excitation signal can also be directed towards the medium 11 without seeking diffusion in the matrix 40.
The depth of each cavity 27, 29 is preferably adapted to the type of fibre it receives, in relation to the above-mentioned considerations. A matrix 50 with two (or even more than two) excitation fibres 10, 10′ is also feasible (
When the above-described device is in use, the surface 22 of the matrix or matrixes is applied against the sample to be analyzed. The fibre or fibres are inserted in the corresponding matrixes, for example before these are positioned against the sample.
According to another embodiment of the invention, of which an example is shown
In this embodiment, the ends of the fibres are also placed, but permanently, at distances H and h which may have the characteristics and/or values explained above. The advantages, in optical terms, are the same as those described above for matrixes having housings in which the fibres are inserted. In particular, the widening effect of the incident beam is the same. Additionally, there is the same advantageous effect with a collection fibre 12 placed permanently in a matrix such as matrix 30, as the advantage described above in connection with
According to one variant of this other embodiment, a device according to the invention comprises a diffusing mass which permanently surrounds the end of one or more optical fibres, and also comprises a housing for the insertion of one or more other optical fibres.
In one preferred embodiment of the invention, implemented for optical analysis, the incident light energy is brought towards the examined medium 11 via a fibre 10 for example. After propagation of the radiation to be analyzed in this medium, the energy is collected by measuring means 4, 13 that are provided e.g. a photomultiplier or camera such as a CCD camera, or CMOS, or CCD array, or one or more avalanche photodiodes, this energy being brought to the detector via a fibre for example or the detector lying distant from the surface 22 but optically coupled with this surface. The assembly used may be the assembly shown
The system may further comprise digital processing means to process measured data e.g. a computer programmed for this purpose. An example of a method for time-resolved analysis of fluorescence imaging signals is given in document EP-1884765. This method can be used to reconstruct an image from a said device.
According to another aspect of the invention, for a medium 11 to be analyzed having certain flexibility or elasticity, better coupling of excitation light energy is obtained if the matrix 30 is slightly pressed into this medium, as illustrated
With respect to living tissues, this is attributed to the fact that blood, responsible for absorption, is then locally expelled by the pressure exerted on the matrix, as indicated by the arrows 55, 57 in
More generally, if the examined medium contains a fluid, a pressure applied to the coupling device of the invention allows this fluid to be repelled or evacuated outside the examined regions, which contributes towards a better measured signal.
Also, to ensure good coupling between a coupling device according to the invention and the examined medium, it is possible to provide a bearing surface 22 having one or more projections or protuberances 22′, 22″ which may have a substantially rounded or convex shape, with no sharp edges as illustrated
The device according to the invention then comprises a contact surface 22 with the medium 11 to be examined, a surface which has at least one non-zero radius of curvature in a plane perpendicular to the surface of this medium.
Said projection or protuberance is a portion or region of material which extends beyond the main bearing surface 22, in the direction of the matter to be analyzed. While the main bearing surface 22 is in contact with surface 11 of the matter to be analyzed, the protuberance enters more deeply into this matter. This forms a region of matter for the matrix 20, a region which will be surrounded by matter to be analyzed, as will be understood from
Preferably, and as illustrated
In this example, the signal collection fibre is located next to the matrix 40.
Signal collection is also reinforced if the fibre 12 is also placed in the matrix (as in
In all cases, the protuberances 22′, 22″ can be in a material identical to the constituent material of the matrix 20.
In all cases, between the surface 22 and the surface of the matter to examined, it is possible to add a liquid preferably having a refractive index close to that of the medium or material. (Viscous for example, e.g. intralipid for further improved coupling). This liquid is preferably transparent and with negligible diffusion. Without this liquid, the application of a pressure to expel the air between the surface 22 of the matrix 20 and the surface 110 of the material to be examined 11 is itself sufficient to allow good coupling to be achieved.
Number | Date | Country | Kind |
---|---|---|---|
09 57029 | Oct 2009 | FR | national |
Number | Name | Date | Kind |
---|---|---|---|
5824023 | Anderson | Oct 1998 | A |
6058324 | Chance | May 2000 | A |
6138046 | Dalton | Oct 2000 | A |
6304771 | Yodh et al. | Oct 2001 | B1 |
6825930 | Cronin et al. | Nov 2004 | B2 |
7304724 | Durkin et al. | Dec 2007 | B2 |
7321791 | Levenson et al. | Jan 2008 | B2 |
7477931 | Hoyt | Jan 2009 | B2 |
7675044 | Laidevant et al. | Mar 2010 | B2 |
8116845 | Hashimshony et al. | Feb 2012 | B2 |
20020072677 | Sevick-Muraca et al. | Jun 2002 | A1 |
20050065440 | Levenson | Mar 2005 | A1 |
20050226548 | Durkin et al. | Oct 2005 | A1 |
20050264805 | Cromwell et al. | Dec 2005 | A1 |
20060149479 | Ma | Jul 2006 | A1 |
20080051665 | Xu et al. | Feb 2008 | A1 |
20080200780 | Schenkman et al. | Aug 2008 | A1 |
20090046291 | Van Der Mark et al. | Feb 2009 | A1 |
20090065710 | Hunziker et al. | Mar 2009 | A1 |
20090131931 | Lee et al. | May 2009 | A1 |
20090141959 | Can et al. | Jun 2009 | A1 |
20090153850 | Nielsen et al. | Jun 2009 | A1 |
20090245611 | Can et al. | Oct 2009 | A1 |
20100155599 | Godavarty et al. | Jun 2010 | A1 |
20110013006 | Uzenbajakava et al. | Jan 2011 | A1 |
20110105865 | Yu et al. | May 2011 | A1 |
Number | Date | Country |
---|---|---|
1 884 765 | Feb 2008 | EP |
2 063 257 | May 2009 | EP |
2 231 958 | Nov 1990 | GB |
10-511875 | Nov 1998 | JP |
2009-148550 | Jul 2009 | JP |
WO 9620638 | Jul 1996 | WO |
WO 9620638 | Jul 1996 | WO |
WO 9626431 | Aug 1996 | WO |
WO 0109605 | Feb 2001 | WO |
WO 0150955 | Jul 2001 | WO |
WO 2005040769 | May 2005 | WO |
WO 2005043138 | May 2005 | WO |
WO 2006032151 | Mar 2006 | WO |
WO 2006087437 | Aug 2006 | WO |
WO 2006135769 | Dec 2006 | WO |
WO 2008132522 | Nov 2008 | WO |
Entry |
---|
French Preliminary Search Report issued May 31, 2010, in Patent Application No. 0957029 (with Translation of Category of Cited Documents in the attached foreign language Search Report). |
Huiyuan He, et al., “An analytic, reflection method for time-domain florescence diffuse optical tomography based on a generalized pulse spectrum technique”, Proceedings of SPIE, vol. 6850, XP 002579460, 2008, pp. 1-8. |
S. R. Arridge, “Optical tomography in medical imaging”, Inverse Problems, vol. 15, No. 2, Apr. 1999, pp. R41-R93. |
Qizhi Zhang, et al., “Three-dimensional diffuse optical tomography of simulated hand joints with a 64 × 64-channel photodiodes-based optical system”, Journal of Optics A: Pure and Applied Optics, vol. 7, No. 5, 2005, pp. 224-231. |
A. Cichocki, et al.,“Multlilayer nonnegative matrix factorisation”, Electronics Letters, vol. 42, No. 16, XP 6027125, Aug. 3, 2006, pp. 1-2. |
Laurent Guyon, et al., “Time-Resolved Fluorescence Tomography in Cancer Research: Backward Versus Toward Geometry”, vol. 7174, XP 002579495, Feb. 12, 2009, pp.1-11. |
Michael S. Patterson, et al., “Time resolved reflectance and transmittance for the non-invasive measurement of tissue optical properties”, Applied Optics, vol. 28, No. 12, Jun. 15, 1989, pp. 2331-2336. |
Jun Wu, et al., “Fluorescence tomographic imaging in turbid media using early-arriving photons and Laplace transforms”, Proceedings of the National Academy of Sciences USA, vol. 94, Aug. 1997, pp. 8783-8788. |
Aurélie Laidevant, et al., “Experimental study of time-resolved measurements on turbid media: determination of optical properties and fluorescent inclusions characterization”, European Conferences on Biomedical Optics, vol. 5859, Jun. 12-16, 2005, pp. 1-9. |
Jean-Marc Dinten, et al., “Performance of different reflectance and diffuse optical imaging tomographic approaches in fluorescence molecular imaging of small animals”, Medical Imaging, Proceedings of SPIE, vol. 6142, 2006, pp. 1-10. |
Anand T. N. Kumar, et al., “Fluorescence-lifetime-based tomography for turbid media”, Optics Letters, vol. 30, No. 24, Dec. 15, 2005, pp. 3347-3349. |
S. Lam, et al., “Time Domain Fluorescent Diffuse Optical Tomography: analytical expressions”, Optics Express, vol. 13, No. 7, Apr. 4, 2005, pp. 2263-2275. |
F. Gao, et al., “Time-Domain Fluorescence Molecular Tomography Based on Generalized Pulse Spectrum Technique”, Proceedings Biomed., 2006, pp. 1-3. |
Jeffrey C. Lagarias, et al., “Convergence Properties of the Nelder-Mead Simplex Method in Low Dimensions”, Society for Industrial and Applied Mathematics, Journal on Optimization, vol. 9, No. 1, 1998, pp. 112-147. |
S. R. Arridge, et al., “The theoretical basis for the determination of optical pathlengths in tissue: temporal and frequency analysis”, Phys. Med. Biol., vol. 37, No. 7, 1992, pp. 1531-1560. |
R. Cubeddu, et al., “Imaging of optical inhomogeneities in highly diffusive media: Discrimination between scattering and absorption contributions”, Appl. Phys. Lett., vol. 69, No. 27, Dec. 30, 1996, pp. 4162-4164. |
Christoph Bremer, et al., “Optical-based molecular imaging: contrast agents and potential medical applications”, Eur. Radiol, vol. 13, 2003, pp. 231-243. |
Anuradha Godavarty, et al., “Three-dimensional fluorescence lifetime tomography”, Med. Phys., vol. 32, No. 4, Apr. 2005, pp. 992-1000. |
Amir H. Gandjbakhche, et al., “Effects of multiple-passage probabilities on fluorescent signals from biological media”, Applied Optics, vol. 36, No. 19, Jul. 1, 1997, pp. 4613-4619. |
David Hall, et al., “Simple time-domain optical method for estimating the depth and concentration of a fluorescent inclusion in a turbid medium”, Optics Letters, vol. 29, No. 19, Oct. 1, 2004, pp. 2258-2260. |
Aurélie Laidevant, et al., “Effects of the surface boundary on the determination of the optical properties of a turbid medium with time-resolved reflectance”, Applied Optics, vol. 45, No. 19, Jul. 1, 2006, pp. 4756-4764. |
Aurélie Laidevant, et al., “Analytical method for localizing a fluorescent inclusion in a turbid medium”, Applied Optics, vol. 46, No. 11, Apr. 10, 2007, pp. 2131-2137. |
Adam Liebert, et al., “Evaluation of optical properties of highly scattering media by moments of distributions of times of flight of photons”, Applied Optics, vol. 42, No. 28, Oct. 1, 2003, pp. 5785-5792. |
Maureen A. O'Leary, “Imaging With Diffuse Photon Density Waves”, Faculties of the University of Pennsylvania, 1996, pp. 1-192. |
Vasilis Ntziachristos, et al., “Experimental three-dimensional fluorescence reconstruction of diffuse media by use of a normalized Born approximation”, Optics Letters, vol. 26, No. 12, Jun. 15, 2001, pp. 893-895. |
Eva M. Sevick-Muraca, et al., “Origin of phosphorescence signals reemitted from tissues”, Optics Letters, vol. 19, No. 23, Dec. 1, 1994, pp. 1928-1930. |
U.S. Appl. No. 14/123,352, filed Dec. 2, 2013, Boutet, et al. |
Office Action mailed Sep. 1, 2014 in Japanese Patent Application No. 2010-227508 (with English-language Translation). |
Number | Date | Country | |
---|---|---|---|
20110085721 A1 | Apr 2011 | US |