|Número de publicación||US6405073 B1|
|Tipo de publicación||Concesión|
|Número de solicitud||US 09/691,554|
|Fecha de publicación||11 Jun 2002|
|Fecha de presentación||18 Oct 2000|
|Fecha de prioridad||22 Jul 1997|
|También publicado como||US6238348|
|Número de publicación||09691554, 691554, US 6405073 B1, US 6405073B1, US-B1-6405073, US6405073 B1, US6405073B1|
|Inventores||Robert J. Crowley, Mark Hamm|
|Cesionario original||Scimed Life Systems, Inc.|
|Exportar cita||BiBTeX, EndNote, RefMan|
|Citas de patentes (109), Otras citas (15), Citada por (60), Clasificaciones (48), Eventos legales (5)|
|Enlaces externos: USPTO, Cesión de USPTO, Espacenet|
This application is a continuation of U.S. patent application Ser. No. 09/167,824, filed Oct. 7, 1998, now U.S. Pat. No. 6,238,348 the entire diclosure of which is corporated herein by reference, and which is further based on, and claims priority to, U.S. Provisional Patent Application Serial No. 60/061,690, filed on Oct. 10, 1997, and is a continuation-in-part of U.S. patent application Ser. No. 08/903,218, filed on Jul. 22, 1997, U.S. patent application Ser. No. 08/898,604, filed on Jul. 22, 1997 now U.S. Pat. No. 6,119,031, U.S. patent application Ser. No. 08/922,263, filed on Sep. 22, 1997, U.S. patent application Ser. No. 08/939,612, filed on Sep. 29, 1997 now U.S. Pat. No. 6,185,443, U.S. patent application Ser. No. 08/940,464, filed on Sep. 29, 1997, U.S. patent application Ser. No. 08/939,707, filed on Sep. 29, 1997 now U.S. Pat. No. 6,096,065, and U.S. patent application Ser. No. 08/939,706, filed on Sep. 29, 1997, now U.S. Pat. No. 5,984,861.
This invention relates to the in situ diagnosis of tissue and organs through the use of interventional spectrometry.
Illumination of tissue can induce endogenous tissue fluorescence, also known as autofluorescence. The spectrum emitted by tissue autofluorescence can be characteristic of a tissue's underlying condition. For example, when illuminated with 370 nm light, the spectrum emitted from normal mucosa differs from that of an adenoma. Tissue autofluorescence spectrometry can thus be employed to diagnose cancerous conditions such as adenoma. Other conditions that can be identified by tissue autofluorescence include arteriosclerosis.
Tissue fluorescence may be based on intrinsic properties of the tissue, or on the differential uptake of a fluorophore administered before the spectrometry is performed.
Interventional tissue autofluorescence spectrometry is known in the art. Currently known devices locate the spectrometer at the proximal end of the interventional device, i.e. outside the patient. These devices rely on fiber optic bundles to transmit light between the analysis site and the externally-located spectrometer. The limitations inherent in employing fiber optic bundles are threefold. First, they are expensive. Second, they are stiff, lacking flexibility and maneuverability. Third, they are large, requiring a relatively large diameter to transmit the necessary amount of light to and from the analysis site. Currently known interventional spectrometry devices are thus limited to use in relatively large and straight passages, such as the gastrointestinal tract.
This invention relates to an interventional device with a spectrometer at its distal end. The spectrometer can be used to perform an in vivo analysis of a tissue's fluorescence characteristics, which can be used in diagnosing conditions such as cancer.
It is an object of this invention to place a spectrometer at the distal end of an interventional device with a small enough form factor to be useful in diagnosing a large variety of tissues and organs in situ.
It is a further object of this invention to provide a means of communication between the distal and proximal ends of the interventional device that is flexible and narrow, thus allowing the device to be used in a variety of passageways throughout the body. It is a further object of the invention that the means of communication be inexpensive, such as a copper wire.
The spectrometer comprises a source unit for emitting light at a certain frequency or a plurality of frequencies. The spectrometer further comprises a plurality of sensors for measuring light at a plurality of frequencies.
The source unit comprises a light source. The light source can be monochromatic or polychromatic. In one embodiment, a tungsten-halogen light is employed as a polychromatic light source. If a polychromatic light source is used, a bandpass filter may be attached. The bandpass filter may allow one or more frequencies to pass through. The frequencies emitted by the source unit are selected to provide data diagnostic of a tissue's condition. In one embodiment, the source unit emits light at a frequency of 435 nm. In other embodiments, the source unit may emit light at a frequency of 420 nm, 490 nm, or any combination thereof.
Similarly, the frequencies measured by the sensors are selected to provide data diagnostic of a tissue's condition. In one embodiment, the spectrometer comprises two sensors, which measure light at wavelengths of 370 nm and 440 nm, respectively.
Another object of this invention is to minimize the waste heat generated by the spectrometer. In one embodiment, the source unit emits 200 μw or less. In another embodiment, the surface of the distal end of the interventional device does not exceed a temperature of 40 degrees Celsius after 30 seconds of continuous operation. In one embodiment of the invention, the source unit is activated in brief pulses in order to keep heat down to a minimum.
FIG. 1 depicts a side-looking embodiment of a spectrometer comprising a 435 nm LED and two sensors.
FIG. 2A is an exploded cross-sectional side view of a clinically-sized end-looking device, with the cross section being taken along line A—A in FIG. 2B.
FIG. 2B is an end of view of the device of FIG. 2A.
FIG. 3 shows the distal end of the clinically-sized device of FIGS. 2A and 2B.
FIG. 4 depicts an electronics block diagram for the clinically-sized device of FIGS. 2A and 2B.
FIG. 5 depicts the emission spectrum of a tungsten-halogen lamp.
FIG. 6 depicts the excitation intensity of a filtered tungsten-halogen lamp.
FIG. 7 depicts a PIN photodiode response as a function of wavelength.
FIG. 8A depicts the wavelengths of light let through a 370 nm bandpass filter.
FIG. 8B depicts the wavelengths of light let through a 400 nm bandpass filter.
FIG. 9 depicts a testbed apparatus.
FIG. 10 depicts the on-channel and off-channel sensitivity of the system depicted in FIG. 9.
FIG. 11 depicts the spectral response of the coumarin fluorophore to 300 nm light.
FIG. 12 depicts the spectral response of the PBD fluorophore to 300 nm light.
FIG. 13 depicts an excitation source response test setup.
FIG. 14 depicts an excitation source inrush and steady-state characteristics.
FIG. 15 depicts the exterior temperature of a probe during and after source excitation.
FIG. 16 depicts two possible geometric configurations for a pair of sensors.
FIG. 17 depicts an excitation source radiation pattern.
FIG. 18 depicts the spatial response of a sensor pair in a coplanar configuration.
FIG. 19 depicts the spatial response of a sensor pair in an angled configuration.
FIG. 20 depicts apparatus for measuring the power output of an excitation source.
FIG. 21 depicts apparatus for measuring sensor efficiency.
In one embodiment, depicted in FIG. 1, the spectrometer 100 is contained in a housing 110 with a diameter of 9.3 F. (0.128 inches) and a wall thickness of 0.015 inches. This embodiment employs as its light source a LED 200 which emits light at a frequency of 435 nm. This embodiment further employs two PIN photodiodes as sensors 150 and 160, disposed on either side of the LED 200. Attached to each sensor 150 and 160 is a bandpass filter 170 and 180 that lets through 370 nm and 440 nm, respectively. The LED and sensors are disposed along the longitudinal axis of the housing 110, and face in a direction perpendicular to the longitudinal axis. In a preferred embodiment, the sensors are angled inward towards the LED 200. The housing 110 is transparent, and is designed to minimize attenuation of both excitation and emitted energy. In a further preferred embodiment, the LED 200 and the PIN photodiodes 150 and 160 are made with single layer construction. In yet another embodiment, the LED 200 is a LEDtronics model 435.
In another embodiment, depicted in FIGS. 2A and 2B, the spectrometer 100 is contained in a housing 110 with a diameter of 0.625 inches, and an overall length of 8 inches. In this embodiment, the light source 120 is a tungsten-halogen bulb 130 with a bichromatic filter 140 attached. The bichromatic filter 140 only lets through light with wavelengths of 420 nm and 490 nm. This embodiment employs two PIN photodiodes 150 and 160 as sensors. Attached to each sensor is a bandpass filter 170 and 180 that lets through 370 nm and 440 nm, respectively. The light source 120 is disposed along the longitudinal axis of the housing 110 and faces the distal end of the housing 110. Similarly, the sensors 150 and 160 face the distal end of the housing, and are disposed on either side of the longitudinal axis. An end cap 190 covers the distal end of the housing. The end cap is designed to minimize attenuation of both excitation and emitted energy. In a preferred embodiment, the sensors are angled inward about 30 degrees towards the longitudinal axis.
In FIG. 3, the sensors 150 and 160, their filters 170 and 180, as well as the light source 120 are visible through the end cap 190.
FIG. 4 depicts an electronics block diagram for the embodiment depicted in FIG. 2 and FIG. 3. In this embodiment, the test sample 400 fluoresces at wavelengths of 440 nm and 370 nm when illuminated by 300 nm light from light source 120. Filters 170 and 180 are attached to PIN photodiodes 150 and 160, respectively. Bandpass filters 170 and 180 let through light of 440 nm and 370 nm, respectively. PIN photodiodes 150 and 160 emit an electrical signal in response to light. The strength of their signals is proportional to the intensity of the light shining on them. These electrical signals are sent through low pass filters 410 and 420. These filters remove 60 Hz electrical signals, and serve to increase the signal-to-noise ratio of the output of the PIN photodiodes 150 and 160. The signals are next sent to amplifiers 430 and 440, and combined into a comparator decision process 450. Depending on the signals' relative intensities, the comparator decision process 450 indicates either result A 460 or result B 470.
In an embodiment of the comparator decision process 450, colonic tissue is diagnosed for adenoma. The colon is illuminated with 325 nm light, and tissue autofluorescence readings are taken at 460 nm and 680 nm. A numeric result, C, is calculated according to the following formula, C=A* (tissue autofluorescence at 460 nm)+B* (tissue autofluorescence at 680 nm), where A and B are constants set according to the relative autofluorescent characteristics of normal and adenomous tissue. If C is above some threshold value, T, then the tissue is diagnosed as an adenoma.
In a preferred embodiment of this invention, the light source operates in the “blue” region of the visible spectrum, emitting light at a wavelength or wavelengths selected from a region between 400 nm and 490 nm.
For the purposes of tissue autofluorescence spectrometry, a light source emitting light at a wavelength of 300 nm is desirable. FIG. 5 depicts the output spectrum of a tungsten-halogen lamp. The units along x-axis 500 represent the wavelength of the light emitted by the light source in nanometers. The units along the y-axis 510 represent the intensity of the light in a.u. The spectrum indicates that the lamp emits a useful amount of light in the 300 nm range.
FIG. 6 depicts output spectra of a tungsten-halogen lamp with a bichromatic filter attached. The units along the x-axis 600 represent the wavelength of the light emitted by the light source in nanometers. The units along the y-axis 610 represent the intensity of the light in a.u. Emission curve 620 depicts the output spectrum when 7V is applied. Emission curve 630 depicts the output spectrum when 6V is applied. Emission curve 640 depicts the output spectrum when 5V is applied. The intensity of the spectrum varies as a result of the voltage used. A large increase in light output at 300 nm is observed when the voltage is increased from 5V to 7V.
For the purposes of this invention, it is necessary that the sensors are able to respond to the light at wavelengths at which the tissues to be examined autofluoresce. FIG. 7 depicts the spectrum response of a PIN photodiode. The units along x-axis 700 represent the wavelength of light input into the sensor in nanometers. The units along the y-axis 710 represent the response of the photodiode in A/W. As evidenced from the response curve 720, the PIN photodiode reacts to a broad spectrum of light.
For the purposes of this invention it is further necessary that a sensor responds only to specific wavelengths of light, and not respond to light outside its designated wavelength. FIG. 8A and FIG. 8B depict two photoresponse curves of a PIN photodiode. The units along the x-axes 800 and 820 represent the wavelength of the light input into the sensor in nanometers. The y-axes 810 and 830 represent the transmission in a.u. FIG. 8A depicts the photoresponse curve of a PIN photodiode with a 370 nm bandpass filter attached. Similarly, FIG. 8B depicts the photoresponse curve of a PIN photodiode with a 400 nm bandpass filter attached. As evidenced by photoresponse curve 840, the PIN photodiode with a 370 nm bandpass filter attached responds only to a narrow range of wavelengths centered around 370 nm. Response to wavelengths outside of this range is essentially zero. Response curve 850 depicts analogous results for the 400 nm bandpass filter.
FIG. 9 depicts a test fixture used to analyze the sensitivity and specificity of the response of the filtered PIN photodiodes. A sample fluorescin is placed in a cuvette 900. A DC power supply powers filtered light source 120. Filtered light source 120 illuminates the sample fluorescin with 300 nm light. The sample fluorescing fluoresces in response to the 300 nm light. Photodiode assemblies 910 and 920 emit electrical signals in response to light of 370 nm and 440 nm, respectively. These electrical signals are sent to channel amplifiers 960 and 970, where the intensities of the electrical signals are read. A fiber optic bundle 930 provides access for an external spectrometer (not shown) to corroborate results. The light source 120, the cuvette 900 and the photodiode assemblies 910 and 920 are all enclosed in a light-tight metal enclosure 950.
FIG. 10 depicts the response of each photodiode assembly to each fluorophore. The units along the x-axis 1040 represent fluorophore concentration as a percentage in solution. The units along the y-axis 1050 represent the response of the photodiodes to the light in nanoamperes. Response curve 1000 depicts the response of the test fixture's 440 nm channel amplifier to coumarin, a 460 nm fluorophore. Response curve 1010 depicts the response of the test fixture's 370 nm channel amplifier to PDB, a 370 nm fluorophore. Response curve 1020 depicts the response of the test fixture's 440 nm channel amplifier to PDB, a 370 nm fluorophore. Response curve 1030 depicts the response of the test fixture's 370 nm channel amplifier to coumarin, a 460 nm fluorophore. Intensity of coumarin fluorescence at decreases at higher concentrations due to self-absorption. These results indicate that each sensor responds to its selected wavelength with a high degree of sensitivity and specificity.
FIG. 11 depicts the emission spectrum of a 0.1% mixture of the fluorescin coumarin to 300 nm light. The units along the x-axis 1100 represent the wavelength of the light emitted in nanometers. The units along the y-axis 1110 represent the intensity of fluorescence in counts. These results indicate that the majority of coumarin's fluorescence is emitted at wavelengths around 460 nm. FIG. 12 depicts the emission spectrum of a 0.1% mixture of the fluorescin PBD to 300 nm light. The units along the x-axis 1200 represent the wavelength of the light emitted in nanometers. The units along the y-axis 1210 represent the intensity of fluorescence in counts. These results indicate that the majority of PBD's fluorescence is emitted at wavelengths around 370 nm.
FIG. 13 depicts the testing apparatus used to analyze inrush and steady state response of the light source 120 to the application of power. The light source 120 is powered by a DC power supply 940 set at 2.0 amps and 37 volts. One channel of an oscilloscope 1300 is placed across a 25 ohm resistor 1310 placed between power supply 940 and light source 120. Photodiode 150 emits an electrical signal in response to the light output by light source 120. The electrical signal is then sent to an amplifier 960 and then to another channel of oscilloscope 1300. Light source 120 and photodiode 150 are enclosed in a light tight container 950. The signals on the two channels of the oscilloscope 1300 are analyzed to compare light output to power input. FIG. 14 depicts the results of these tests. Response curve 1400 depicts the intensity of the light emitted by the light source 120. Response curve 1410 depicts the current supplied to the light source 120. From these tests, it was determined that the spectrometer would require a power supply of 10.64 watts, and that it took 400 milliseconds from the application of power for the light source to reach full intensity.
For in vivo use, surface temperature needs to be moderate. FIG. 15 depicts probe surface temperature as a function of time of operation. The units along the x-axis 1500 represent time in seconds. The units along the y-axis 1510 represent the surface temperature of the probe in degrees Celsius. To obtain these measurements, a J-type thermocouple (Omega Engineering, Inc., Stamford, Conn.) model 5TC-GG-J-20-36 was attached to the exterior surface of the embodiment depicted in FIG. 3. The tungsten-halogen bulb 130 of this embodiment has been demonstrated to generate a surface temperature of no more than 40 degrees Celsius after 30 seconds of continuous operation. To prevent an undue increase in surface temperature, the light source 120 can be operated intermittently or with short excitation times.
The spatial characteristics of the sensors effect the sensitivity of the spectrometer. FIG. 16 depicts two possible spatial configurations for an array pair 1600 of sensors. FIG. 16(a) depicts the array pair 1600 as coplanar, while FIG. 16(b) depicts the array pair 1600 angled inwards toward the light source (not shown). FIG. 17 depicts the radiation pattern of the excitation source. FIG. 18 depicts the response pattern for an array pair in a coplanar configuration. FIG. 19 depicts the response pattern for an array pair in an inwardly angled configuration. These results indicate that angling the array pair may improve system sensitivity.
The spectrometer must be able to operate within certain parameters so as not to cause tissue damage. For example, it is desirable to keep the surface temperature of the spectrometer to a minimum. In order to minimize waste heat generated by the spectrometer, it is therefore desirable to obtain fluorescence readings with the minimal amount of excitation energy. FIG. 20 depicts apparatus used to measure the power output of an excitation energy source, such as a light source. In this apparatus, the light source 120 and its filter 140 is attached to a Newport radiometer head 1720 by means of an adapter 1700. The detector 1710 measures the power output of the light source 120. In a preferred embodiment of the spectrometer, the sensors are able to obtain fluorescence readings using an excitation energy as low as 200 μW.
FIG. 21 depicts a test fixture used to measure the response and efficiency of the PIN photodiodes. A baseline value was first obtained by shining light source 120 onto reflectance standard 1800 and measuring reflected light using an advanced PhotonX detector 1820. The reflectance standard was then replaced with an uncalibrated fluorescence standard and the unfiltered photodiode 1820 was replaced with a photodiode with a bandpass filter centered at 442 nm. A fluorescence signal of 4.1 nW was recorded, which is about 10% of the reflected signal from a white target.
While certain embodiments have been used to illustrate the invention, it will be recognized by those skilled in the art that various modifications can be made therein without departing from the scope of the invention as claimed.
|Patente citada||Fecha de presentación||Fecha de publicación||Solicitante||Título|
|US2002559||13 Abr 1932||28 May 1935||Charles Wappler Frederick||Means for surgical resection|
|US2583937||9 Sep 1947||29 Ene 1952||Surgical exploring and operating|
|US3176114||16 Jul 1962||30 Mar 1965||Kneisley Richard F||Device for removing nasal hair|
|US4075475 *||3 May 1976||21 Feb 1978||Chemetron Corporation||Programmed thermal degradation-mass spectrometry analysis method facilitating identification of a biological specimen|
|US4233493||9 Dic 1977||11 Nov 1980||Nath Guenther||Apparatus for applying intense light radiation to a limited area|
|US4274706||30 Ago 1979||23 Jun 1981||Hughes Aircraft Company||Wavelength multiplexer/demultiplexer for optical circuits|
|US4289966||10 Abr 1980||15 Sep 1981||The United States Of America As Represented By The Secretary Of The Army||Radiation energy detector and analyzer|
|US4340307||7 Jul 1980||20 Jul 1982||Beckman Instruments, Inc.||Bichromatic spectrophotometer with wavelength reversal|
|US4472728||19 Feb 1982||18 Sep 1984||The United States Of America As Represented By The Administrator Of The National Aeronautics And Space Administration||Imaging X-ray spectrometer|
|US4541272||13 May 1983||17 Sep 1985||Roland Bause||Electronically controlled fuel injection system|
|US4548505||19 Abr 1982||22 Oct 1985||Sumitomo Electric Industries, Ltd.||Sensor for spectral analyzer for living tissues|
|US4556057||11 Mar 1983||3 Dic 1985||Hamamatsu Tv Co., Ltd.||Cancer diagnosis device utilizing laser beam pulses|
|US4570638||14 Oct 1983||18 Feb 1986||Somanetics Corporation||Method and apparatus for spectral transmissibility examination and analysis|
|US4672972||10 Sep 1986||16 Jun 1987||Berke Howard R||Solid state NMR probe|
|US4718417||22 Mar 1985||12 Ene 1988||Massachusetts Institute Of Technology||Visible fluorescence spectral diagnostic for laser angiosurgery|
|US4872458||8 Sep 1987||10 Oct 1989||Olympus Optical Co., Ltd.||Thermotherapy apparatus|
|US4882623||11 Ago 1988||21 Nov 1989||Olympus Optical Co., Ltd.||Signal processing apparatus for endoscope capable of changing outline enhancement frequency|
|US4894547||28 Sep 1987||16 Ene 1990||Yale University||Optical method and apparatus for detecting and measuring aging, photoaging, dermal disease and pigmentation in skin|
|US4902896||8 May 1987||20 Feb 1990||Mine Safety Appliances Company||Infrared fluid analyzer|
|US4928172||15 Sep 1988||22 May 1990||Olympus Optical Co., Ltd.||Endoscope output signal control device and endoscope apparatus making use of the same|
|US4930516||25 Abr 1988||5 Jun 1990||Alfano Robert R||Method for detecting cancerous tissue using visible native luminescence|
|US4938602||27 Mar 1989||3 Jul 1990||Electronic Instrumentation And Technology, Inc.||Automated process monitoring|
|US4981138||30 Jun 1988||1 Ene 1991||Yale University||Endoscopic fiberoptic fluorescence spectrometer|
|US5001556||22 Mar 1990||19 Mar 1991||Olympus Optical Co., Ltd.||Endoscope apparatus for processing a picture image of an object based on a selected wavelength range|
|US5009655||24 May 1989||23 Abr 1991||C. R. Bard, Inc.||Hot tip device with optical diagnostic capability|
|US5021888||15 Dic 1988||4 Jun 1991||Kabushiki Kaisha Toshiba||Miniaturized solid state imaging device|
|US5034010||22 Sep 1989||23 Jul 1991||Massachusetts Institute Of Technology||Optical shield for a laser catheter|
|US5036853||24 Ago 1989||6 Ago 1991||Polartechnics Ltd.||Physiological probe|
|US5042494||4 Dic 1989||27 Ago 1991||Alfano Robert R||Method and apparatus for detecting cancerous tissue using luminescence excitation spectra|
|US5045056||15 Sep 1989||3 Sep 1991||Behl Robert S||Method and device for thermal ablation of hollow body organs|
|US5056503||28 Feb 1991||15 Oct 1991||Olympus Optical Co., Ltd.||Endoscope with high frequency accessory and reduced video interference|
|US5062428||11 Feb 1991||5 Nov 1991||Nim Incorporated||Method and device for in vivo diagnosis detecting IR emission by body organ|
|US5106387||21 Sep 1989||21 Abr 1992||Massachusetts Institute Of Technology||Method for spectroscopic diagnosis of tissue|
|US5115137||21 Feb 1990||19 May 1992||Spectraphos Ab||Diagnosis by means of fluorescent light emission from tissue|
|US5116759||27 Jun 1990||26 May 1992||Fiberchem Inc.||Reservoir chemical sensors|
|US5125404||21 Nov 1989||30 Jun 1992||Massachusetts Institute Of Technology||Apparatus and method for obtaining spectrally resolved spatial images of tissue|
|US5127407||13 Nov 1990||7 Jul 1992||Critikon, Inc.||Epidural oxygen sensor|
|US5131398||22 Ene 1990||21 Jul 1992||Mediscience Technology Corp.||Method and apparatus for distinguishing cancerous tissue from benign tumor tissue, benign tissue or normal tissue using native fluorescence|
|US5166755||23 May 1990||24 Nov 1992||Nahum Gat||Spectrometer apparatus|
|US5172693||16 Ene 1990||22 Dic 1992||Doody Michael C||Prenatal non-invasive detection of meconium stained amniotic fluid|
|US5174297||20 Nov 1990||29 Dic 1992||S.L.T. Japan Co., Ltd.||Diagnostic apparatus for living tissues and medical treatment apparatus with diagnostic apparatus|
|US5187572||30 Oct 1991||16 Feb 1993||Olympus Optical Co., Ltd.||Endoscope system with a plurality of synchronized light source apparatuses|
|US5187672||22 Ene 1991||16 Feb 1993||Nim Incorporated||Phase modulation spectroscopic system|
|US5193542||25 Mar 1992||16 Mar 1993||Missanelli John S||Peripartum oximetric monitoring apparatus|
|US5197470||16 Jul 1990||30 Mar 1993||Eastman Kodak Company||Near infrared diagnostic method and instrument|
|US5201318||4 Oct 1991||13 Abr 1993||Rava Richard P||Contour mapping of spectral diagnostics|
|US5206174||24 Sep 1992||27 Abr 1993||Eg&G Idaho, Inc.||Method of photon spectral analysis|
|US5213569||31 Mar 1992||25 May 1993||Davis Peter L||Tip for a tissue phacoemulsification device|
|US5233621||9 Oct 1992||3 Ago 1993||Intellectual Property Development Associates Of Connecticut, Inc.||Second harmonic generation and self frequency doubling laser materials comprised of bulk germanosilicate and aluminosilicate glasses|
|US5242437||7 Jun 1989||7 Sep 1993||Trimedyne Laser Systems, Inc.||Medical device applying localized high intensity light and heat, particularly for destruction of the endometrium|
|US5261410||7 Feb 1991||16 Nov 1993||Alfano Robert R||Method for determining if a tissue is a malignant tumor tissue, a benign tumor tissue, or a normal or benign tissue using Raman spectroscopy|
|US5262645||3 Sep 1991||16 Nov 1993||General Motors Corporation||Sensor for measuring alcohol content of alcohol gasoline fuel mixtures|
|US5304173||20 Jul 1993||19 Abr 1994||Massachusetts Institute Of Technology||Spectral diagonostic and treatment system|
|US5305748||5 Jun 1992||26 Abr 1994||Wilk Peter J||Medical diagnostic system and related method|
|US5309907||26 Ago 1992||10 May 1994||Siemens Aktiengesellschaft||Measuring arrangement for examining a subject with visible, NIR or IR light|
|US5318024||16 Dic 1991||7 Jun 1994||Massachusetts Institute Of Technology||Laser endoscope for spectroscopic imaging|
|US5348018||25 Nov 1991||20 Sep 1994||Alfano Robert R||Method for determining if tissue is malignant as opposed to non-malignant using time-resolved fluorescence spectroscopy|
|US5350375||15 Mar 1993||27 Sep 1994||Yale University||Methods for laser induced fluorescence intensity feedback control during laser angioplasty|
|US5351532||8 Oct 1992||4 Oct 1994||Paradigm Technologies||Methods and apparatus for making chemical concentration measurements in a sub-surface exploration probe|
|US5377676||30 Mar 1993||3 Ene 1995||Cedars-Sinai Medical Center||Method for determining the biodistribution of substances using fluorescence spectroscopy|
|US5383467||18 Nov 1992||24 Ene 1995||Spectrascience, Inc.||Guidewire catheter and apparatus for diagnostic imaging|
|US5386827||30 Mar 1993||7 Feb 1995||Nim Incorporated||Quantitative and qualitative in vivo tissue examination using time resolved spectroscopy|
|US5398844||31 Ene 1994||21 Mar 1995||Boston Scientific Corporation||Multiple ligating band dispenser|
|US5402778||19 Ene 1993||4 Abr 1995||Nim Incorporated||Spectrophotometric examination of tissue of small dimension|
|US5402792||15 Mar 1994||4 Abr 1995||Shimadzu Corporation||Ultrasonic medical apparatus|
|US5405369||25 Ene 1994||11 Abr 1995||Medical College Of Ohio||Photochemical ablation of gastro-intestinal tissue for augmentation of an organ|
|US5413108||21 Abr 1993||9 May 1995||The Research Foundation Of City College Of New York||Method and apparatus for mapping a tissue sample for and distinguishing different regions thereof based on luminescence measurements of cancer-indicative native fluorophor|
|US5417207||6 Dic 1993||23 May 1995||Sensor Devices, Inc.||Apparatus for the invasive use of oximeter probes|
|US5419323||17 Nov 1989||30 May 1995||Massachusetts Institute Of Technology||Method for laser induced fluorescence of tissue|
|US5421337||29 Mar 1994||6 Jun 1995||Massachusetts Institute Of Technology||Spectral diagnosis of diseased tissue|
|US5421339||12 May 1993||6 Jun 1995||Board Of Regents, The University Of Texas System||Diagnosis of dysplasia using laser induced fluoroescence|
|US5445608||16 Ago 1993||29 Ago 1995||James C. Chen||Method and apparatus for providing light-activated therapy|
|US5452723||24 Jul 1992||26 Sep 1995||Massachusetts Institute Of Technology||Calibrated spectrographic imaging|
|US5456252||30 Sep 1993||10 Oct 1995||Cedars-Sinai Medical Center||Induced fluorescence spectroscopy blood perfusion and pH monitor and method|
|US5461229||6 Jun 1994||24 Oct 1995||Unisys Corporation||On-the-go optical spectroscopy soil analyzer|
|US5467767||27 Ago 1993||21 Nov 1995||Alfano; Robert R.||Method for determining if tissue is malignant as opposed to non-malignant using time-resolved fluorescence spectroscopy|
|US5512757||6 Abr 1992||30 Abr 1996||Rosemount Analytical, Inc.||Spectrophotometer and optical system therefor|
|US5517313||21 Feb 1995||14 May 1996||Colvin, Jr.; Arthur E.||Fluorescent optical sensor|
|US5542928||27 Jun 1994||6 Ago 1996||Innerdyne, Inc.||Method and device for thermal ablation having improved heat transfer|
|US5545897||4 Oct 1994||13 Ago 1996||Santa Barbara Research Center||Optically-based chemical detection system|
|US5553614||14 Jun 1993||10 Sep 1996||Non-Invasive Technology, Inc.||Examination of biological tissue using frequency domain spectroscopy|
|US5555885||16 Jul 1993||17 Sep 1996||Non-Invasive Technology, Inc.||Examination of breast tissue using time-resolved spectroscopy|
|US5556421||22 Feb 1995||17 Sep 1996||Intermedics, Inc.||Implantable medical device with enclosed physiological parameter sensors or telemetry link|
|US5562100||25 May 1994||8 Oct 1996||Massachusetts Institute Of Technology||Method for laser induced fluorescence of tissue|
|US5571152||26 May 1995||5 Nov 1996||Light Sciences Limited Partnership||Microminiature illuminator for administering photodynamic therapy|
|US5579773||30 Sep 1994||3 Dic 1996||Martin Marietta Energy Systems, Inc.||Laser-induced differential normalized fluorescence method for cancer diagnosis|
|US5632740||7 Sep 1994||27 May 1997||Ceram Optec Industries, Inc.||Illuminated leading probe device|
|US5647368||28 Feb 1996||15 Jul 1997||Xillix Technologies Corp.||Imaging system for detecting diseased tissue using native fluorsecence in the gastrointestinal and respiratory tract|
|US5769791||7 Jun 1995||23 Jun 1998||Sextant Medical Corporation||Tissue interrogating device and methods|
|US5785658 *||7 Jun 1995||28 Jul 1998||Sexant Medical Corporation||In vivo tissue analysis methods and apparatus|
|US5785704 *||29 Jul 1996||28 Jul 1998||Mrc Systems Gmbh||Method for performing stereotactic laser surgery|
|US5807261||7 Jun 1995||15 Sep 1998||Sextant Medical Corporation||Noninvasive system for characterizing tissue in vivo|
|US5984861 *||29 Sep 1997||16 Nov 1999||Boston Scientific Corporation||Endofluorescence imaging module for an endoscope|
|US6026331 *||19 Jul 1994||15 Feb 2000||Microsulis Limited||Treatment apparatus|
|US6119031 *||22 Jul 1997||12 Sep 2000||Boston Scientific Corporation||Miniature spectrometer|
|US6129667 *||2 Feb 1998||10 Oct 2000||General Electric Company||Luminal diagnostics employing spectral analysis|
|US6185443 *||29 Sep 1997||6 Feb 2001||Boston Scientific Corporation||Visible display for an interventional device|
|US6238348 *||7 Oct 1998||29 May 2001||Scimed Life Systems, Inc.||Miniature spectrometer system and method|
|DE888727C||22 Abr 1941||3 Sep 1953||Quarzlampen Gmbh||Koerperhoehlenbestrahlungslampe|
|DE3023130A1||20 Jun 1980||21 Ene 1982||Bluecher Hubert||Mouth and nose steriliser - uses high intensity light flash of millisecond duration|
|DE4005743A1||23 Feb 1990||29 Ago 1991||Wolf Gmbh Richard||Lithotriptor to destroy gallstones intra-or trans-luminally - has shock-wave generator, lead contg. incompressible material, and opt balloon to press generator against gall bladder|
|DE19512518A1||4 Abr 1995||5 Oct 1995||Akira Fujishima||Gerät zur Behandlung von Tumoren|
|EP0304321A1||19 Ago 1988||22 Feb 1989||Paul Okimoto||Vaginal testing applicator and method|
|EP0314937A2||7 Oct 1988||10 May 1989||Pacesetter AB||Implantable blood oxygen sensor and method of use|
|EP0629380A1||4 Sep 1991||21 Dic 1994||Angiomedics Ii, Inc.||Inhibition of restenosis by ultraviolet radiation|
|EP0650694A1||31 Oct 1994||3 May 1995||Polartechnics Ltd||Method and apparatus for diseased tissue type recognition|
|EP0728440A2||26 Feb 1996||28 Ago 1996||Ott, Lutz||Method and device for deep, selective, non-invasive detection of muscle activity|
|EP0777119A2||16 Nov 1996||4 Jun 1997||Boehringer Mannheim Gmbh||Apparatus for light reflection measurements|
|EP0792618B1||31 Ene 1997||8 Oct 2003||Xillix Technologies Corporation||Imaging system for detecting diseased tissue using native fluorescence in the gastrointestinal and respiratory tract|
|1||Anidjar et al., "Ultraviolet Laser-Induced Autofluorescence Distinction Between Malignant and Normal Urothelial Cells and Tissues", Jour. of Biomedical Optics, 1(3), pp. 335-341, Jul. 1996.|
|2||Bolliger, et al., LESIT Final Report, 1995.|
|3||Coleman et al., "Acoustic Emission and Sonoluminescence Due to Cavitation at the Beam Focus of an Electrohydraulic Shock Wave Lithotripter", Ultrasound in Med. & Biol., vol. 18, No. 3, pp. 267-281, 1992.|
|4||Cothren et al., "Gastrointestinal Tissue Diagnosis by Laser-Induced Fluorescence Spectroscopy at Endoscopy", Gastrointestinal Endoscopy, vol. 36, No. 2, 1990.|
|5||Crowley et al., "Ultrasound Guided Therapeutic Catheters: Recent Developments and Clinical Results", International Jour. of Cardiac Imaging, vol. 6, pp. 145-156, 1991.|
|6||Huang et al., "Fluorescence Diagnosis of Gynecological Cancerous and Normal Tissues", SPIE, vo. 2135.|
|7||Kapadia et al., "Laser-Induced Fluorescence Spectroscopy of Human Colonic Mucosa", Gastroenterology, vol. 99, No. 1, pp. 150-157.|
|8||Ko, "Biomedical Sensors and Actuators", Electronics Engineers' Handbook, Fink and Christiansen, eds. 26-53-26-58, 1989.|
|9||Ko, "Biomedical Sensors and Actuators", Electronics Engineers' Handbook, Fink and Christiansen, eds. 26-53—26-58, 1989.|
|10||Kopp et al., "Stay Tuned: Photonic Filters Color Your World", Photonic Design & Solutions.|
|11||Lilge et al., "Light Induced Fluorescence Spectroscopy at Endoscopy," presented at the 10th Asian Pacific Congress of Gastroenterology.|
|12||Meindl, "Implantable Telemetry in Biomedical Research" Electronics Engineers' Handbook, Fink and Christiansen, eds. pp. 26-41-26-53, 1989.|
|13||Meindl, "Implantable Telemetry in Biomedical Research" Electronics Engineers' Handbook, Fink and Christiansen, eds. pp. 26-41—26-53, 1989.|
|14||Petrofsky, "In Vivo Measurement of Brain Blood Flow in the Cat", IEEE Transactions on Biomedical Engineering, vol. BME-26, No. 8, Aug. 1979.|
|15||Vona et al., "A Test of the Hypothesis that Cavitation at the Focal Area of an Extracorporeal Shock Wave Lithotripter Produces far Ultraviolet and Soft X-Ray Emissions", J. Acoust. Soc. Am., 98(2), Pt.1, Aug. 1995.|
|Patente citante||Fecha de presentación||Fecha de publicación||Solicitante||Título|
|US6882875 *||18 Oct 2000||19 Abr 2005||Boston Scientific Corporation||Visible display for an interventional device|
|US7291824||22 Dic 2005||6 Nov 2007||Palo Alto Research Center Incorporated||Photosensing throughout energy range and in subranges|
|US7315667||22 Dic 2005||1 Ene 2008||Palo Alto Research Center Incorporated||Propagating light to be sensed|
|US7358476||22 Dic 2005||15 Abr 2008||Palo Alto Research Center Incorporated||Sensing photons from objects in channels|
|US7386199||22 Dic 2005||10 Jun 2008||Palo Alto Research Center Incorporated||Providing light to channels or portions|
|US7420677||22 Dic 2005||2 Sep 2008||Palo Alto Research Center Incorporated||Sensing photon energies of optical signals|
|US7433552||22 Dic 2005||7 Oct 2008||Palo Alto Research Center Incorporated||Obtaining analyte information|
|US7522786||22 Dic 2005||21 Abr 2009||Palo Alto Research Center Incorporated||Transmitting light with photon energy information|
|US7547904||22 Dic 2005||16 Jun 2009||Palo Alto Research Center Incorporated||Sensing photon energies emanating from channels or moving objects|
|US7817274||5 May 2008||19 Oct 2010||Jingyun Zhang||Compact spectrometer|
|US7937148||3 May 2011||Nanostim, Inc.||Rate responsive leadless cardiac pacemaker|
|US7945333||13 Oct 2006||17 May 2011||Nanostim, Inc.||Programmer for biostimulator system|
|US8010209||30 Ago 2011||Nanostim, Inc.||Delivery system for implantable biostimulator|
|US8126531||13 Dic 2001||28 Feb 2012||Boston Scientific Scimed, Inc.||Miniature spectrometer|
|US8140148||9 Ene 2007||20 Mar 2012||Boston Scientific Scimed Ltd.||Readable probe array for in vivo use|
|US8295939||23 Oct 2012||Nanostim, Inc.||Programmer for biostimulator system|
|US8345226||14 Nov 2008||1 Ene 2013||Jingyun Zhang||Spectrometers miniaturized for working with cellular phones and other portable electronic devices|
|US8352025||13 Oct 2006||8 Ene 2013||Nanostim, Inc.||Leadless cardiac pacemaker triggered by conductive communication|
|US8373860||19 Abr 2010||12 Feb 2013||Palo Alto Research Center Incorporated||Transmitting/reflecting emanating light with time variation|
|US8437582||23 Mar 2009||7 May 2013||Palo Alto Research Center Incorporated||Transmitting light with lateral variation|
|US8457742||13 Oct 2006||4 Jun 2013||Nanostim, Inc.||Leadless cardiac pacemaker system for usage in combination with an implantable cardioverter-defibrillator|
|US8527068||2 Feb 2010||3 Sep 2013||Nanostim, Inc.||Leadless cardiac pacemaker with secondary fixation capability|
|US8537343||13 Nov 2012||17 Sep 2013||Jingyun Zhang||Spectrometer miniaturized for working with cellular phones and other portable electronic devices|
|US8543205||12 Oct 2011||24 Sep 2013||Nanostim, Inc.||Temperature sensor for a leadless cardiac pacemaker|
|US8594470||7 May 2013||26 Nov 2013||Palo Alto Research Center Incorporated||Transmittting light with lateral variation|
|US8615310||13 Dic 2011||24 Dic 2013||Pacesetter, Inc.||Delivery catheter systems and methods|
|US8629981||20 May 2011||14 Ene 2014||Palo Alto Research Center Incorporated||Analyzers with time variation based on color-coded spatial modulation|
|US8660637||24 Ene 2012||25 Feb 2014||Boston Scientific Scimed, Inc.||Miniature spectrometer|
|US8723140||9 Ago 2011||13 May 2014||Palo Alto Research Center Incorporated||Particle analyzer with spatial modulation and long lifetime bioprobes|
|US8788035||7 Dic 2012||22 Jul 2014||Pacesetter, Inc.||Leadless cardiac pacemaker triggered by conductive communication|
|US8788053||17 Oct 2012||22 Jul 2014||Pacesetter, Inc.||Programmer for biostimulator system|
|US8798745||19 Abr 2013||5 Ago 2014||Pacesetter, Inc.||Leadless cardiac pacemaker system for usage in combination with an implantable cardioverter-defibrillator|
|US8821799||26 Ene 2007||2 Sep 2014||Palo Alto Research Center Incorporated||Method and system implementing spatially modulated excitation or emission for particle characterization with enhanced sensitivity|
|US8855789||26 Jul 2011||7 Oct 2014||Pacesetter, Inc.||Implantable biostimulator delivery system|
|US9020611||12 Oct 2011||28 Abr 2015||Pacesetter, Inc.||Leadless cardiac pacemaker with anti-unscrewing feature|
|US9029800||9 Ago 2011||12 May 2015||Palo Alto Research Center Incorporated||Compact analyzer with spatial modulation and multiple intensity modulated excitation sources|
|US9060692||23 May 2013||23 Jun 2015||Pacesetter, Inc.||Temperature sensor for a leadless cardiac pacemaker|
|US9072913||29 Abr 2011||7 Jul 2015||Pacesetter, Inc.||Rate responsive leadless cardiac pacemaker|
|US9126032||13 Dic 2011||8 Sep 2015||Pacesetter, Inc.||Pacemaker retrieval systems and methods|
|US9164037||26 Ene 2007||20 Oct 2015||Palo Alto Research Center Incorporated||Method and system for evaluation of signals received from spatially modulated excitation and emission to accurately determine particle positions and distances|
|US9168383||19 Oct 2011||27 Oct 2015||Pacesetter, Inc.||Leadless cardiac pacemaker with conducted communication|
|US9192774||27 Jun 2014||24 Nov 2015||Pacesetter, Inc.||Cardiac pacemaker system for usage in combination with an implantable cardioverter-defibrillator|
|US9216298||13 Oct 2006||22 Dic 2015||Pacesetter, Inc.||Leadless cardiac pacemaker system with conductive communication|
|US9227077||23 Nov 2010||5 Ene 2016||Pacesetter, Inc.||Leadless cardiac pacemaker triggered by conductive communication|
|US9242102||20 Dic 2011||26 Ene 2016||Pacesetter, Inc.||Leadless pacemaker with radial fixation mechanism|
|US20010029328 *||14 Jun 2001||11 Oct 2001||Crowley Robert J.||Readable probe array for in-vivo use|
|US20020115918 *||13 Dic 2001||22 Ago 2002||Crowley Robert J.||Miniature spectrometer|
|US20050165288 *||27 Ene 2004||28 Jul 2005||Scimed Life Systems, Inc.||Systems and methods for treating breast tissue|
|US20070145236 *||22 Dic 2005||28 Jun 2007||Palo Alto Research Center Incorporated||Photosensing throughout energy range and in subranges|
|US20070145249 *||22 Dic 2005||28 Jun 2007||Palo Alto Research Center Incorporated||Sensing photons from objects in channels|
|US20070146704 *||22 Dic 2005||28 Jun 2007||Palo Alto Research Center Incorporated||Sensing photon energies emanating from channels or moving objects|
|US20070146888 *||22 Dic 2005||28 Jun 2007||Palo Alto Research Center Incorporated||Propagating light to be sensed|
|US20070147189 *||22 Dic 2005||28 Jun 2007||Palo Alto Research Center Incorporated||Sensing photon energies of optical signals|
|US20070147726 *||22 Dic 2005||28 Jun 2007||Palo Alto Research Center Incorporated||Transmitting light with photon energy information|
|US20070147728 *||22 Dic 2005||28 Jun 2007||Palo Alto Research Center Incorporated||Providing light to channels or portions|
|US20070148760 *||22 Dic 2005||28 Jun 2007||Palo Alto Research Center Incorporated||Obtaining analyte information|
|US20080183418 *||26 Ene 2007||31 Jul 2008||Palo Alto Research Center Incorporated||Method and system for evaluation of signals received from spatially modulated excitation and emission to accurately determine particle positions and distances|
|US20090118601 *||29 Sep 2005||7 May 2009||University Of Delaware||Ir spectrographic apparatus and method for diagnosis of disease|
|US20090220189 *||23 Mar 2009||3 Sep 2009||Palo Alto Research Center Incorporated||Transmitting Light with Lateral Variation|
|EP1880664A2 *||12 Feb 2004||23 Ene 2008||Medtronic, Inc.||Implantable chemical sensor|
|Clasificación de EE.UU.||600/476|
|Clasificación internacional||G01J3/12, G01N21/25, A61B1/00, G01N21/31, A61B5/07, A61B18/24, A61B17/22, A61B18/00, G01N21/33, A61B5/00, A61N5/06, A61B6/00, A61B5/03, A61B18/18|
|Clasificación cooperativa||G01N21/25, G01N21/33, A61N5/0601, A61B5/0084, A61B18/24, A61B18/00, A61B5/0071, A61B18/18, A61B5/00, A61B2017/22021, G01N2021/3166, G01J2003/1213, A61N2005/0661, A61B5/0031, A61B5/6848, A61N5/062, A61B5/0075, A61B2018/1807, A61B5/073, A61B5/036|
|Clasificación europea||A61B5/68D1B, A61B5/00P12B, A61N5/06C8, A61B5/00P5, A61B5/00P7, A61B5/00B9, A61N5/06B, G01N21/25, G01N21/33, A61B5/00, A61B18/00, A61B18/18, A61B18/24|
|27 May 2003||CC||Certificate of correction|
|25 Abr 2005||AS||Assignment|
|23 Nov 2005||FPAY||Fee payment|
Year of fee payment: 4
|20 Nov 2009||FPAY||Fee payment|
Year of fee payment: 8
|13 Nov 2013||FPAY||Fee payment|
Year of fee payment: 12