WO2000041611A2 - System and method for controlling tissue ablation - Google Patents
System and method for controlling tissue ablation Download PDFInfo
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- WO2000041611A2 WO2000041611A2 PCT/US2000/000460 US0000460W WO0041611A2 WO 2000041611 A2 WO2000041611 A2 WO 2000041611A2 US 0000460 W US0000460 W US 0000460W WO 0041611 A2 WO0041611 A2 WO 0041611A2
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- tissue
- accordance
- ablative
- interface
- alter
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
- A61B18/04—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by heating
- A61B18/12—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by heating by passing a current through the tissue to be heated, e.g. high-frequency current
- A61B18/1206—Generators therefor
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
- A61B2017/00017—Electrical control of surgical instruments
- A61B2017/00022—Sensing or detecting at the treatment site
- A61B2017/00057—Light
- A61B2017/00061—Light spectrum
Definitions
- This invention relates generally to systems and methods for controlling medical devices, and more particularly, to a control system and methods for controlling tissue ablation.
- Fluoroscopy is known but is two-dimensional and exposes the patient and medical personnel to various forms of radiation. Impaired visualization of the surgical field makes removal of diseased tissue difficult.
- high energy tissue ablation devices such as those powered by lasers, radio frequency transmission, microwaves and the like, is risky under conditions of impaired visualization because poor discrimination of healthy tissue from diseased tissue can result in damage of healthy tissue. Accordingly, a surgeon operating such an ablation device must advance it extremely cautiously, perhaps missing diseased tissue which should be removed .
- tissue ablative devices It would therefore be desirable to provide a precise and reliable method for controlling the activation and advancement of tissue ablative devices. It would also be desirable to provide an improved method for visualizing internal body tissues being treated with minimally invasive tissue ablative devices. It would also be desirable to provide an improved method and apparatus for differentiation of abnormal tissue from normal tissue.
- a method for controlling tissue ablation uses optical time domain reflectometry data to differentiate abnormal tissue from normal tissue, to control ablation of abnormal tissue by controlling the delivery of energy to a tissue ablation element.
- a control system uses data provided by an interferometric apparatus, to provide control signals to tissue ablative apparatus and controls activation of the tissue ablation apparatus so that normal tissue is left untreated while abnormal tissue is ablated.
- the present invention is directed to using interference data to identify an interface between abnormal tissue and healthy or normal tissue, and altering the delivery of energy to the tissue ablative apparatus in response to identification of an interface.
- the control system includes a microprocessor and an energy controller.
- the control system is coupled to an interferometric apparatus for providing interfering light beams which produce the interferometric data. More specifically, for example, a low coherence light source producing a light beam is coupled to a beam splitter which splits the beam into two beams, a first or reference beam, and a second or sampling beam, which are transmitted respectively down a first optical fiber, and a second optical fiber.
- the second optical fiber extends through the lumen of a support member such as a catheter so that a distal, sampling end of the second optical fiber can be positioned near a sample, such as an internal body tissue to be inspected.
- the first optical fiber is positioned outside the body.
- the first beam is reflected at the distal or free end of the first optical fiber by a reflector coupled thereto, while the second beam is reflected at the distal sampling end by the sample.
- the lengths of the first and second optical fibers are adjustable with, for example, a piezoelectric coil.
- the reflected beams interfere with one another when recombined at the beam splitter.
- the path length difference between the recombined beams produces a pattern of interference which is detected by a detecting element coupled to the beam splitter.
- the detecting element provides the interference data to the control system, in which the microprocessor generates a psuedoimage of the sample, and detects interfaces between normal and abnormal tissue. In response to the detection of such an interface, the microprocessor generates and supplies control signals to the energy controller, which accordingly alters the delivery of energy to the tissue ablative apparatus.
- the present invention is directed to providing a psuedoimage of a tissue sample for visual display to an individual who is manually advancing a tissue ablative element of the tissue ablative apparatus.
- the microprocessor is coupled to an output display device such as a monitor.
- the psuedoimage data generated by the microprocessor is displayed on the monitor so that the operator has a visual image while manually advancing the tissue ablative element.
- the operator can advance while watching the image until, for example, the control system detects an interface and alters the delivery of energy to the tissue ablative apparatus.
- control system and method provide for minimally invasive control of tissue ablation. Further, the system provides high resolution image data so that tissue ablation can be controlled at a very fine scale. In addition, the system and method provide for improved differentiation of abnormal tissue from normal tissue.
- Figure 1 is a schematic illustration of a control system for controlling tissue ablation.
- Figure 2 is a schematic illustration of the principles of optical coherence domain reflectometry on which the control system for controlling tissue ablation is based.
- Figure 3 is a graph showing the scattering effects on a light beam of a diseased artery having a layer of atheroscleotic plaque.
- Figure 4 is a graph showing the scattering effects on a light beam of a healthy artery.
- FIG 1 is a schematic illustration of an exemplary embodiment of a control system 100.
- control system 100 includes a microprocessor 102 coupled to an energy controller 104, and is shown in Figure 1 coupled to interoferometric apparatus 106 and tissue ablative apparatus 108.
- Microprocessor 102 utilizing an output supplied by interferometric apparatus 106, generates an output signal which is supplied to energy controller 104.
- energy controller 104 uses the output signal supplied by microprocessor 102, energy controller 104 alters, or adjusts, an energy signal supplied to tissue ablative apparatus 108.
- the output of microprocessor 102 can be used to generate a pseudoimage on an output device as described below.
- microprocessor 102 A control algorithm as described below may be implemented in microprocessor 102 and practiced using data collected by interoferometric apparatus 106. It will be apparent to those skilled in the art that, of course, such an algorithm may be practiced with many alternative microprocessors, and is not limited to practice only in connection with those integrated circuits referred to in the art as microprocessors. Therefore, and as used herein, the term microprocessor refers to microcomputers, processors, microcontrollers, application-specific integrated circuits, and other programmable circuits. In addition, the present application is directed to the control methods and system as described below in more detail. It should be understood that such methods and systems should not be limited to a particular interferometric apparatus or tissue ablative apparatus as described below in an exemplary embodiment.
- Interferometric apparatus 106 typically includes a light source 110 coupled to a beam splitter 112.
- light source 110 is a low coherence light source having a power of about 100 microWatts to about 25 milliwatts. While the light source may be varied, sources that emit short coherent wavelengths of about 0.7 to about 2.0 microns are more desirable than those emitting longer wavelengths because shorter wavelengths allow better imaging properties and penetration. However, the light source may be varied to adjust the wavelength of the light to between about 03 to about 5.0 microns, to optimize the imaging resolution of the tissue expected to be encountered.
- a first, reference optical fiber 1 14 is coupled at a proximal end 116 to beam splitter 112, and has a free or distal end 118 with a reflector 120, such as a mirrored surface, coupled thereto.
- a second, sampling optical fiber 122 is coupled at a proximal end 124 to beam splitter 112, and has a distal sampling end 126 for placement near or adjacent an internal body tissue T.
- first optical fiber 114 is wrapped around a first piezoelectric coil 128, and second optical fiber 122 is wrapped around a second piezoelectric coil 130.
- Second optical fiber 122 extends through a lumen of a support member 132 such as, for example, a catheter or an endoscope.
- Beam splitter 112 has an output coupled to a detecting element 134 which includes, for example, a photodetector, a demodulator and an analog digitizer (not shown).
- Detecting element 134 has an output coupled to microprocessor 102.
- Microprocessor 102 can be further coupled to an output display device 136 such as a computer monitor for visual display of data.
- First optical fiber 114 and second optical fiber 122 are, for example, a type commonly used in medical imaging, having a total outside diameter of less than about 150 microns.
- suitable optical fibers are fabricated from drawn or extruded glass or plastic having a central core and a cladding of a lower refractive index material to promote internal reflection.
- the diameter of the optical fibers may be varied to optimize transmission of the particular wavelength of light chosen, and to obtain clearance through the lumen of support member 132. For example, for light having a wavelength of 1300 nm, a single mode optical fiber having a diameter of 125 microns with a total outside diameter of about 150 microns would be suitable.
- Optical fibers having smaller diameters of about 80 microns are also available and can be used when greater clearance through the lumen of support member 132 is desired, or alternatively, bundles of optical fibers may be used.
- Tissue ablative apparatus 108 in one embodiment, includes an energy source 138 such as a laser energy source, for tissue ablation.
- Energy source 138 is coupled to a tissue ablative device 140 at a proximal end 142 of tissue ablative element 140.
- Tissue ablative element 140 can be, for example, a laser catheter.
- tissue ablative element 140 has a distal end 144 and extends through support member 132 so that distal end 144 can be positioned near tissue T.
- energy source 138 for tissue ablative element 140 is a laser source
- tissue ablative element 140 is a laser catheter including at least one optical fiber (not shown) extending through support member 132 for transmitting a laser beam from the laser source to tissue T, so that tissue inspection and ablation can be accomplished simultaneously.
- energy source 138 is again a laser source
- ablative element 140 shares first optic fiber 114 with interoferometric apparatus 106, and input to first optic fiber 114 is switched with a second beam splitter (not shown) between interoferometric apparatus 106 and the laser source so that inspection of tissue T and ablation occur alternately.
- tissue ablative element 140 may be, for example, a radio frequency device, mechanical cutting or atherectomy device, ultrasound device, microwave device or other minimally invasive tissue ablation device.
- Energy source 138 can accordingly be a radiofrequency source, source for mechanical energy, ultrasound source, microwave source, or the like.
- Figure 2 is a schematic illustration of the principles of optical coherence domain reflectometry on which control system 100 is based.
- support member 132 is positioned internally in a body, for example by inserting into a body passage or surgical incision, so that second optic fiber distal end 126 is positioned within the body near tissue T to be inspected.
- First optic fiber 114 is positioned external to the body.
- Light source 110 is energized to produce a light beam B which is transmitted to beam splitter 112.
- Beam splitter 112 is configured to split beam B from light source 110 into a reference beam B, and a sampling beam B 2 .
- Beam splitter 112 directs reference beam B j along first optical fiber 114 toward reflector 120, and second beam B 2 along second optical fiber 122 toward tissue T. B, is reflected back along first optical fiber 114 by reflector 120, and B 2 is reflected back along second optical fiber 122 by tissue T. B, and B 2 are recombined at beam splitter 112 and interfere constructively with each other when their respective path lengths are equivalent with one another.
- the distance over which interference occurs can be determined by the coherence function of the light source.
- the coherence length is about 15 microns for a low coherence light source having a power of about 100 microWatts to about 25 milliWatts.
- the optical path length of light beam B 2 depends on the length of second optical fiber 122.
- the optical path length of light beam B depends on the length of first optical fiber 114 and the distance in the tissue from where the light is scattered (reflected), adjusted for the change in the group refractive index difference of the tissue.
- the optical distances along optical fibers 114 and 122 can be varied by actuating piezoelectric coils 128 and 130. By continually varying the optical path lengths, the tissue depth can be scanned such that the intensity of light scattering from a series of specific depths can be measured.
- the interferometric technique precisely measures very small distances and thicknesses, so that a high resolution image of tissue T can be formed, providing on-line, high resolution information to determine if ablative device 140 can be safely enabled or advanced. Further details on the interferometric technique and interferometric apparatus are described in co-pending U.S. Patent Application Serial Nos.
- control system 100 is instead coupled to an apparatus which uses a different technique for analyzing reflected light, such as Raman or Rayleigh spectroscopy, induced fluorescence, or other linear or nonlinear techniques.
- microprocessor 102 uses analysis of spectroscopic data to identify an interface between abnormal and normal tissue.
- Figure 3 is a graph showing the scattering effects on light beam B 2 of an abnormal tissue: an area of plaque 302 in a diseased artery.
- the graph shows intensity of reflected light in decibels as a function of distance from distal end 126 of second optical fiber 122.
- plaque area 302 is distinguishable from an area 304 of normal, healthy artery tissue by an increased and steady decay of reflected light intensity as a function of distance. More specifically, by determining the slope of the decay, abnormal tissue is identified as described below in more detail.
- the steady decay exhibited in area 302 relative to area 304 is attributable to the relatively unorganized structure of abnormal tissue, in this case plaque, which tends to scatter light in random directions, thereby decreasing the intensity of reflected light transmitted back through second optical fiber 122.
- the relatively more organized structure of normal tissue, in this case healthy arterial wall scatters the light in a birefringent or anisotropic pattern so that relatively more light is reflected back through second optical fiber 122.
- Microprocessor 102 supplies control signals to energy controller 104. More specifically, the control algorithm detects the presence of abnormal tissue by examining the rate of decay of reflected light intensity as a function of distance from distal end 126 of second optical fiber 122. For example, microprocessor 102 samples the reflected light at about 10 hertz, and generates a sliding average of multiple points, for example averaging the intensity value over a window of about 8 to about 30 points at a time. The sliding average identifies inflection points in the function which represent a true or actual change in the slope of the function, as opposed to noise. An actual change in slope identifies an interface between normal tissue and abnormal tissue.
- normal tissue is identified by regions of the function having a slope of less than about -75 dB/mm. Regions of the function having a slope within the range of about -75 dB/mm to about -150 dB/mm indicate a soft plaque such as a fatty or lipid plaque. A slope within about -150 dB/mm to about -200 dB/mm would indicate a calcified plaque, while a slope greater than about -200 dB/mm indicates air or blood.
- the algorithm is, for example, a simple go/no-go algorithm in which the inflection points between regions of the function having different slopes are used to determine the state of control signals supplied to energy controller 104 to either enable or disenable tissue ablative device 140.
- the algorithm can be configured to perform a more complex pattern recognition or noise analysis which identifies the changes in reflected light which characterize the interfaces between normal and abnormal tissue.
- Figure 3 shows reflected light intensity as a function of distance in an artery, using a light source of about 100 microWatts emitting light at a wavelength of 1300 nm.
- the slope of the function is less than about -75 dB/mm, which indicates normal, healthy tissue in area 304.
- the slope of the function changes, which microprocessor 102 identifies as an interface between normal tissue (arterial wall) and abnormal tissue, in this case a plaque.
- the slope of the function from about 0.200 mm to about 0.275 mm, plaque area 302, from distal end 126 is about -100 dB/mm. This slope falls within the range of about -75 dB/mm to about -150 dB/mm, which indicates a soft plaque such as a fatty or lipid plaque.
- the slope of the function again changes, and microprocessor 102 identifies an interface.
- the slope of the function from about 0.275 mm to about 0.350 mm from distal end 126 is about -267 dB/mm, indicating air or blood, so that microprocessor 102 identifies an interface between the end of a plaque and air or blood at 0.275 mm from distal end 126.
- a change in slope representing a decrease in decay of reflected light as a function of distance i.e. a decrease in slope
- Figure 4 shows the intensity of reflected light as a function of distance in a normal, healthy artery, using a light source of about 100 microWatts emitting light at a wavelength of 1300 nm.
- the function from about 0J00 mm to about 0.230 mm from distal end 126 has a slope of about -70 dB/mm, indicating normal tissue.
- the slope of the function from about 0.230 mm to about 0.290 mm increases to about -400 db/m , indicating blood in the artery.
- distal end 144 of disenabled tissue ablative element 140 is positioned within a normal section of artery and advanced along a longitudinal axis of the artery defined by the length of second optical fiber 122.
- the start of an area or region of abnormal tissue is identified when microprocessor 102 identifies a normal tissue/abnormal tissue interface ahead of second optic fiber distal end 126 (and distal end 144 of tissue ablative element 140). Tissue ablative element distal end 144 is advanced just past the interface, e.g. , the start of the plaque, and then microprocessor 102 supplies signals to energy controller 104 to activate energy source 138 so that tissue ablative device 140 is enabled and the abnormal tissue (plaque) is ablated. In one embodiment, to insure that normal tissue is not inadvertently damaged, a small area or region of plaque behind the area where ablative element 140 is first enabled can be left remaining.
- Tissue ablative element 140 is advanced through the plaque, and can be safely enabled as long as no tissue interface between the abnormal tissue (plaque) and normal tissue is detected by microprocessor 102.
- microprocessor 102 using the output of interferometric apparatus 106, identifies an interface between the abnormal (plaque) tissue and normal tissue ahead of second optic fiber distal end 126, microprocessor 102 accordingly supplies signals to energy controller 104 to deactivate energy source 138 so that tissue ablative element 140 is disenabled before reaching the normal tissue, and normal tissue is undamaged by tissue ablative element 140.
- tissue ablative element 140 A small area or region of plaque at the end of the plaque relative to tissue ablative element distal end 144 may be left remaining, to insure that normal tissue is undamaged by tissue ablative element 140.
- tissue ablative element 140 the relative position of tissue ablative element 140 with respect to an abnormal/normal or normal/abnormal tissue interface, at which tissue ablative element 140 is enabled or disenabled, can be varied.
- the amount of energy delivered to tissue ablative element 140 can be adjusted depending on whether a soft plaque or calcified plaque has been identified. For example, if a calcified plaque is identified, a lower amount of energy can first be delivered to tissue ablative element 140.
- control system 100 performs real-time control of tissue ablation without further input from an operator.
- control system 100 is further linked to a stepping motor or the like, which is linked to tissue ablative element 140 and to microprocessor 102.
- the stepping motor responds to control signals from microprocessor 102 by advancing or retracting tissue ablative element 140 so that both enablement and advancement of tissue ablative element 140 are automatically controlled by control system 100. For example, after abnormal tissue has been detected and tissue ablative element 140 enabled, tissue ablative element 140 is advanced as long as a tissue interface between the abnormal tissue and normal tissue is not detected.
- Tissue ablative element 140 continues to advance until such a tissue interface is identified, indicating normal tissue ahead of tissue ablative element 140. Once such an interface is identified, tissue ablative element 140 is disenabled and can be retracted.
- a manual operator of tissue ablative element 140 may view the pseudoimage on output display device 136 for real-time imaging of the tissue so that the operator can accordingly respond by manually activating or deactivating the energy controller, or by manually advancing or retracting ablative element 140. Because second optical fiber 122 can be used simultaneously and side-by-side with tissue ablative element 140, the system can provide continuous, high resolution imaging data to the operator as tissue ablative element 140 is advanced.
- control system thus provides high resolution imaging data for automated or manual control of minimally invasive tissue ablative devices.
- tissue ablative modalities, devices and probes including radio frequency devices, microwave devices, ultrasound devices, mechanical cutting or atherectomy devices and laser catheters, as known in the art, are used with control system 100.
- the guidance system can be used simultaneously with the tissue ablative element to provide continuous online information regarding the tissue being treated, as the tissue ablative element is being advanced.
Abstract
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Priority Applications (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP00904259A EP1146930B1 (en) | 1999-01-09 | 2000-01-07 | System for controlling tissue ablation |
AT00904259T ATE548078T1 (en) | 1999-01-09 | 2000-01-07 | SYSTEM FOR CONTROLLING TISSUE ABLATION |
JP2000593228A JP4226788B2 (en) | 1999-01-09 | 2000-01-07 | System and method for controlling tissue ablation |
BR0007419-5A BR0007419A (en) | 1999-01-09 | 2000-01-07 | Control system to control a tissue ablation apparatus, and tissue ablation system to remove tissue ablation |
CA002355835A CA2355835A1 (en) | 1999-01-09 | 2000-01-07 | System and method for controlling tissue ablation |
AU26044/00A AU769737B2 (en) | 1999-01-09 | 2000-01-07 | System and method for controlling tissue ablation |
IL14418300A IL144183A (en) | 1999-01-09 | 2000-01-07 | System and method for controlling tissue ablation |
HK02102564.0A HK1040648A1 (en) | 1999-01-09 | 2002-04-06 | System and method for controlling tissue ablation |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US09/228,030 | 1999-01-09 | ||
US09/228,030 US6228076B1 (en) | 1999-01-09 | 1999-01-09 | System and method for controlling tissue ablation |
Publications (2)
Publication Number | Publication Date |
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WO2000041611A2 true WO2000041611A2 (en) | 2000-07-20 |
WO2000041611A3 WO2000041611A3 (en) | 2000-11-30 |
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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PCT/US2000/000460 WO2000041611A2 (en) | 1999-01-09 | 2000-01-07 | System and method for controlling tissue ablation |
Country Status (11)
Country | Link |
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US (1) | US6228076B1 (en) |
EP (1) | EP1146930B1 (en) |
JP (1) | JP4226788B2 (en) |
KR (1) | KR100623212B1 (en) |
AT (1) | ATE548078T1 (en) |
AU (1) | AU769737B2 (en) |
BR (1) | BR0007419A (en) |
CA (1) | CA2355835A1 (en) |
HK (1) | HK1040648A1 (en) |
IL (1) | IL144183A (en) |
WO (1) | WO2000041611A2 (en) |
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- 2000-01-07 AT AT00904259T patent/ATE548078T1/en active
- 2000-01-07 AU AU26044/00A patent/AU769737B2/en not_active Ceased
- 2000-01-07 KR KR1020017008636A patent/KR100623212B1/en not_active IP Right Cessation
- 2000-01-07 JP JP2000593228A patent/JP4226788B2/en not_active Expired - Fee Related
- 2000-01-07 WO PCT/US2000/000460 patent/WO2000041611A2/en active IP Right Grant
- 2000-01-07 EP EP00904259A patent/EP1146930B1/en not_active Expired - Lifetime
- 2000-01-07 CA CA002355835A patent/CA2355835A1/en not_active Abandoned
- 2000-01-07 BR BR0007419-5A patent/BR0007419A/en not_active Application Discontinuation
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Cited By (9)
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EP2595586A2 (en) * | 2010-07-20 | 2013-05-29 | The Johns Hopkins University | Surface tracking and motion compensating surgical tool system |
EP2595586A4 (en) * | 2010-07-20 | 2014-11-26 | Univ Johns Hopkins | Surface tracking and motion compensating surgical tool system |
US10322194B2 (en) | 2012-08-31 | 2019-06-18 | Sloan-Kettering Institute For Cancer Research | Particles, methods and uses thereof |
US10105456B2 (en) | 2012-12-19 | 2018-10-23 | Sloan-Kettering Institute For Cancer Research | Multimodal particles, methods and uses thereof |
US10888227B2 (en) | 2013-02-20 | 2021-01-12 | Memorial Sloan Kettering Cancer Center | Raman-triggered ablation/resection systems and methods |
US10912947B2 (en) | 2014-03-04 | 2021-02-09 | Memorial Sloan Kettering Cancer Center | Systems and methods for treatment of disease via application of mechanical force by controlled rotation of nanoparticles inside cells |
US10688202B2 (en) | 2014-07-28 | 2020-06-23 | Memorial Sloan-Kettering Cancer Center | Metal(loid) chalcogen nanoparticles as universal binders for medical isotopes |
WO2016028749A1 (en) * | 2014-08-20 | 2016-02-25 | Memorial Sloan Kettering Cancer Center | Raman-triggered ablation/resection systems and methods |
US10919089B2 (en) | 2015-07-01 | 2021-02-16 | Memorial Sloan Kettering Cancer Center | Anisotropic particles, methods and uses thereof |
Also Published As
Publication number | Publication date |
---|---|
EP1146930A4 (en) | 2003-02-19 |
ATE548078T1 (en) | 2012-03-15 |
US6228076B1 (en) | 2001-05-08 |
KR20010101426A (en) | 2001-11-14 |
KR100623212B1 (en) | 2006-09-12 |
CA2355835A1 (en) | 2000-07-20 |
JP4226788B2 (en) | 2009-02-18 |
HK1040648A1 (en) | 2002-06-21 |
BR0007419A (en) | 2001-10-16 |
IL144183A (en) | 2005-12-18 |
WO2000041611A3 (en) | 2000-11-30 |
EP1146930A2 (en) | 2001-10-24 |
EP1146930B1 (en) | 2012-03-07 |
AU769737B2 (en) | 2004-02-05 |
JP2002534199A (en) | 2002-10-15 |
IL144183A0 (en) | 2002-05-23 |
AU2604400A (en) | 2000-08-01 |
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