Apparatus and system for ablative treatment

Abstract

Various methods, systems, and devices for treating tissue ablation are disclosed. Some embodiments disclosed herein relate to methods for treating tumors, systems used to irradiate tissue and tumors with electromagnetic radiation, components and devices of the systems, and kits for providing systems used to irradiate tissue and tumors with electromagnetic radiation. In some embodiments, the systems can provide sub-ablative infrared radiation that can be absorbed by nanoparticles. In some embodiments, the nanoparticles absorb the radiation and convert it to thermal energy. In some embodiments, even though the infrared radiation itself is sub-ablative, the thermal energy generated by the nanoparticles is sufficient to cause thermal coagulation, hyperthermia, and / or tissue ablation.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This patent application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 174,431, filed April 13, 2021, which is incorporated by reference in its entirety for all purposes.

[0002] Methods, systems, kits, and devices for delivery of nanoparticles for therapeutic ablation treatment are disclosed. [Background technology]

[0003] Thermal and radiological ablation can be used to burn and / or ablate tissue for therapeutic purposes. These techniques can be used to ablate cancerous tissue or tumors. Summary of the Invention [Problem to be solved by the invention]

[0004] Some embodiments disclosed herein relate to methods, systems, kits, and devices for therapeutic treatment and / or ablation therapy of tissue. Some embodiments disclosed herein relate to a laser delivery assembly. The laser delivery assembly, or laser catheter, is a device configured to receive a laser waveguide (such as an optical fiber). In some embodiments, the laser delivery assembly is a cooled laser delivery assembly configured to receive a coolant for cooling the laser waveguide during operation. In some embodiments, the laser delivery device assembly may include a body and a probe. In some embodiments, the laser delivery device assembly may include a sheath connector. It has been found that using a sheath connector provides certain advantages.

[0005] In some embodiments, the body can include a first fluid chamber. In some embodiments, the body can include a first hub. In some embodiments, the first hub can be in fluid communication with the first fluid chamber. In some embodiments, the first hub can include a first fluid port. In some embodiments, the first hub can include a fitting configured to engage a first coolant line.

[0006] In some embodiments, the body can include a second fluid chamber. In some embodiments, the second fluid chamber can include a waveguide opening. In some embodiments, the body can include a second hub. In some embodiments, the second hub can be in fluid communication with the second fluid chamber. In some embodiments, the second hub can include a second fluid port. In some embodiments, the second hub can include a fitting configured to engage a second coolant line. In some embodiments, the body can include a waveguide hub. In some embodiments, the waveguide hub provides access to the second fluid chamber of the body. In some embodiments, the waveguide hub can be configured to receive a waveguide and direct the waveguide through the second fluid chamber and the waveguide opening of the second fluid chamber.

[0007] In some embodiments, the probe extends distally from the body. In some embodiments, the probe may include an elongated probe member. In some embodiments, the elongated probe member may include a flexible outer wall. In some embodiments, the flexible outer wall defines a tubular cavity within the elongated probe. In some embodiments, the outer wall The wall defines a first lumen capable of fluid communication with the first fluid chamber. In some embodiments, the flexible outer wall extends distally from the body. In some embodiments, the elongate probe member may include a proximal portion and a distal portion. In some embodiments, the proximal portion may be located closer to the body than the distal portion (e.g., may be adjacent, may be attached, etc.). In some embodiments, the distal portion comprises a sealed tip (e.g., the elongate probe member terminates in a sealed tip).

[0008] In some embodiments, the probe can include an inner tubular member. In some embodiments, the inner tubular member extends distally from the body into a tubular cavity of the elongated probe member. In some embodiments, the inner tubular member defines a second lumen of the probe. In some embodiments, the inner tubular member can include an exit opening. In some embodiments, the exit opening can be disposed within a distal portion of the elongated probe member. In some embodiments, the inner tubular member can be configured to receive the waveguide when the waveguide is directed through the waveguide opening.

[0009] In some embodiments, the sheath connector can include a fitting. In some embodiments, the sheath connector can be configured to engage with a corresponding connector (e.g., a fitting) of the catheter sheath. In some embodiments, the catheter sheath can be configured to at least partially cover the probe when connected to the sheath connector via the catheter sheath connector. In some embodiments, the catheter sheath stabilizes the probe when the sheath connector is connected to the connector sheath via the catheter sheath connector. In some embodiments, the catheter sheath reduces the incidence of probe kinking when the sheath connector is connected to the connector sheath via the catheter sheath connector. In some embodiments, when the sheath connector is connected to the connector sheath via the catheter sheath connector, the laser irradiation device assembly can be held by the probe in a position where the probe is horizontal without kinking the probe when the sheath connector is connected to the connector sheath via the catheter sheath connector.

[0010] In some embodiments, the sheath connector can be circumferentially disposed around at least a portion of the elongated probe member. In some embodiments, the sheath connector can be connected to and / or integral with the body of the laser applicator assembly. In some embodiments, the sheath connector can be connected to and / or integral with the elongated probe member.

[0011] In some embodiments, the length of the probe can be graduated. In some embodiments, the graduations can be on a proximal portion of the probe. In some embodiments, the graduations are optionally absent from a distal portion of the probe. In some embodiments, the graduations on the probe begin at or near the sheath connector. In some embodiments, the graduations on the probe can be approximately 4 mm apart. In some embodiments, the probe can be of a material that can be transparent to visible wavelengths of light, infrared light, ultraviolet light, or combinations thereof. In some embodiments, the sealed tip can be a domed tip. In some embodiments, the domed tip can be transparent to visible wavelengths of light, infrared light, ultraviolet light, or combinations of the foregoing.

[0012] In some embodiments, a waveguide can be disposed within the second lumen and configured to transmit laser radiation through the dome-shaped tip of the introducer probe when received by the laser irradiator assembly.

[0013] In some embodiments, the first lumen of the probe is in fluid communication with the second lumen of the probe. In some embodiments, the first chamber can be in fluid communication with the second fluid chamber via the probe.

[0014] In some embodiments, the probe can include a reservoir located between the sealed tip and the exit opening of the inner tubular member, the reservoir configured to allow circulation and / or movement of fluid between the first and second lumens of the probe.

[0015] Some embodiments relate to a laser applicator assembly including a body, a sheath connector, and a probe. In some embodiments, the probe can include an elongated probe member extending distally from the body, the elongated probe including a first lumen and a sealed end. In some embodiments, the probe can include an inner tubular member extending distally. In some embodiments, the inner tubular member can be disposed and / or positioned within a first lumen of the introducer probe. In some embodiments, the inner tubular member can include a second lumen and terminate at an exit opening within the elongated probe. In some embodiments, the first lumen can be in fluid communication with the second lumen. In some embodiments, the sheath connector can be configured to engage with a corresponding connector of the catheter sheath. In some embodiments, the catheter sheath can be configured to at least partially cover the probe when connected to the sheath connector via the connector of the catheter sheath. In some embodiments, the catheter sheath stabilizes the probe when the sheath connector is connectable to the connector sheath via the connector of the catheter sheath. In some embodiments, the catheter sheath can reduce the incidence of kinking of the probe if the sheath connector is connectable to the connector sheath via the catheter sheath connector. In some embodiments, the length of the probe can be graduated. In some embodiments, the graduations can be provided on a proximal portion of the probe. In some embodiments, the graduations are optionally not provided on a distal portion of the probe. In some embodiments, the sealed end of the probe can be a dome-shaped surface configured to allow transmission of laser light.

[0016] In some embodiments, the laser applicator assembly can include a first hub in fluid communication with the first lumen. In some embodiments, the first hub can include a first fluid port and a fitting configured to engage the first coolant line. In some embodiments, the laser applicator assembly can include a second hub in fluid communication with the second lumen. In some embodiments, the second hub can include a second fluid port and a fitting configured to engage the second coolant line.

[0017] Any of the embodiments described above, or elsewhere in this specification, can include one or more of the following features.

[0018] In some embodiments, the first fluid port can be a coolant outlet configured to distribute coolant to a first coolant line, and the second fluid port can be a coolant inlet configured to receive coolant from the second coolant line.

[0019] In some embodiments, the laser applicator assembly can be configured to pass coolant from the coolant inlet, through the second lumen to the first lumen, and out the coolant outlet.

[0020] In some embodiments, the fluid inlet and fluid outlet may be configured to interface with different connectors to prevent improper routing of coolant through the laser illuminator.

[0021] In some embodiments, the mating of the first hub can be a male or female connector. The mating of the second hub can be a male or female connector, and the gender of the connector of the first hub and the connector of the second hub can be different genders.

[0022] In some embodiments, the sheath connector can be threaded and configured to engage corresponding threads on the connector of the catheter sheath.

[0023] In some embodiments, the sheath connector can include a luer fitting configured to engage with a corresponding luer fitting of the catheter sheath connector, hi some embodiments, the sheath connector can include a male luer fitting configured to engage with a corresponding female luer fitting of the catheter sheath connector.

[0024] Some embodiments relate to a system including a laser applicator assembly as described above or elsewhere herein. In some embodiments, the system may further include a waveguide, a catheter sheath, or both. In some embodiments, the catheter sheath may be graduated along at least a portion of its length. In some embodiments, the graduations may be provided on the catheter sheath in proximity to the connector of the catheter sheath.

[0025] In some embodiments, the probe can be longer than the catheter sheath. In some optional embodiments, the probe can protrude from the catheter sheath when the catheter sheath can be connected to the laser applicator assembly via the sheath connector and the catheter sheath connector. In some embodiments, the exit opening of the inner tubular member can be optionally not covered by the catheter sheath when the catheter sheath is connected to the laser applicator assembly via the sheath connector and the catheter sheath connector.

[0026] In some embodiments, the waveguide can include a connector fitting configured to mate with a corresponding fitting on the waveguide hub. In some embodiments, the waveguide can be an optical fiber. In some embodiments, the optical fiber can include a diffusing portion configured to distribute radiation from the optical fiber out of the laser irradiation device assembly.

[0027] In some embodiments, the system may further include a first coolant line. In some embodiments, the system may further include a second coolant line. In some embodiments, the system may further include a coolant reservoir configured to engage the second coolant line and to be in fluid communication with the laser irradiator assembly when engaged with the second coolant line, the coolant reservoir configured to supply coolant to the laser irradiator assembly. In some embodiments, the system may further include a pump configured to convey coolant from the coolant reservoir through the second line to the laser irradiator assembly to cool the waveguide during operation. In some embodiments, the system may further include a coolant collection bag configured to engage the first coolant line and to be in fluid communication with the laser irradiator assembly when engaged with the first coolant line, the coolant collection bag may be configured to receive coolant from the laser irradiator assembly.

[0028] In some embodiments, the laser illumination system may include a laser source configured in optical communication with the optical fiber. In some embodiments, the ablation may be configured to transmit radiation through the optical fiber to the laser illuminator assembly. In some embodiments, when activated, the ablation transmits electromagnetic radiation through the optical fiber and through the sealed end. Send a line.

[0029] Some embodiments relate to a kit including a laser delivery device assembly as disclosed above or elsewhere herein.Some embodiments relate to a kit including a system as disclosed above or elsewhere herein.

[0030] Some embodiments relate to a method of treating a tumor. In some embodiments, the method can include systemically injecting nanoparticles into a patient, the nanoparticles being adapted to convert infrared light into thermal energy. In some embodiments, the method can include causing the nanoparticles to preferentially accumulate in the tumor. In some embodiments, the method can include inserting a trocar assembly including a trocar and a catheter sheath into the patient at a first insertion point. In some embodiments, the trocar assembly can be sheathed within the catheter sheath. In some embodiments, the method can include positioning a trocar assembly within the patient by passing the trocar assembly through the tumor such that the trocar assembly passes through a proximal aspect of the tumor and terminates distally of the tumor, forming a first pathway within the tumor. In some embodiments, the method can include removing the trocar from the trocar assembly while leaving the catheter sheath within the patient within the first pathway. In some embodiments, the method can include inserting a probe of a laser applicator assembly into the catheter sheath. In some embodiments, the method can include guiding the probe to a first location within a first path within the tumor, the first location can be located distal to or near the tumor. In some embodiments, the method can include connecting the catheter sheath to the laser applicator assembly using a sheath connector. In some embodiments, the method can include activating a laser source connected to a waveguide within the probe when the probe is at the first location within the first path to generate infrared radiation for a first time at the first location, thereby heating the nanoparticles to an ablation temperature. In some embodiments, the method can include decoupling the catheter sheath from the laser applicator assembly. In some embodiments, the method can include withdrawing the probe to a second location within the first path within the tumor, the second location being located proximal to the first location.In some embodiments, the method can include connecting the catheter sheath to a laser delivery device assembly with a sheath connector. In some embodiments, the method can include activating the laser light source when the probe is in the second position to generate infrared radiation for a second period of time, thereby heating the nanoparticles to an ablation temperature.

[0031] In some embodiments, the method can include removing the catheter sheath and the probe from the first path and forming a second path through the tumor using the trocar assembly. In some embodiments, the method can include removing the trocar from the trocar assembly while leaving the catheter sheath in the patient in the second path. In some embodiments, the method can include inserting a probe of the laser illuminator assembly into the catheter sheath. In some embodiments, the method can include guiding the probe to a first location in the second path in the tumor, the first location can be distal or proximate to the tumor. In some embodiments, the method can include connecting the catheter sheath to the laser illuminator assembly with a sheath connector. In some embodiments, the method can include activating the ablation when the probe can be in the first location in the second path to generate infrared radiation for a third period of time, thereby heating the nanoparticles to an ablation temperature.

[0032] In some embodiments, the first and second locations of the first pathway can be about 8 mm apart. In some embodiments, a template grid can be used to position the trocar assembly at the first and second insertion locations.

[0033] In some embodiments, the method may include inserting a trocar assembly into the patient at an additional insertion point, which may be positioned laterally proximal to the tumor from the first insertion point and the second insertion point.

[0034] In some embodiments, a template grid can be used to position the trocar assembly at additional insertion points. In some embodiments, the laser can be activated to emit radiation that is insufficient to induce photothermal coagulation of tissue.

[0035] In some embodiments, the method can include activating the laser illuminator to a sub-ablative level. In some embodiments, the laser illuminator can be activated to emit sub-ablative radiation in the absence of nanoparticles. In some embodiments, the laser illuminator can be activated to emit about 3.5 W / cm to about 4.5 W / cm of radiation at the diffuser tip.

[0036] Some embodiments relate to a method of treating a tumor. In some embodiments, the method may include obtaining a laser delivery device assembly as disclosed elsewhere herein. In some embodiments, the method may include positioning a catheter sheath in tissue that constitutes the tumor by passing the catheter sheath from a proximal surface of the tissue to a distal side of the tissue to a first position. In some embodiments, the method may include inserting a probe of the laser delivery device assembly into the catheter sheath. In some embodiments, the method may include connecting the catheter sheath to the laser delivery device assembly with a sheath connector. In some embodiments, the method may include activating an ablation of the laser delivery device assembly while the probe is in the first position to deliver sub-ablative infrared radiation to the tissue for a first period of time.

[0037] In some embodiments, the method can include withdrawing the probe while connected to the catheter sheath to a second location within the tissue, the second location being proximal to the first location. In some embodiments, the method can include activating ablation when the introducer probe is in the second location to irradiate the tissue with sub-ablative infrared radiation for a second period of time.

[0038] In some embodiments, the catheter sheath can be calibrated, and the calibrated scale on the catheter sheath can be used to measure the distance between the first location and the second location.

[0039] In some embodiments, the method can include decoupling the catheter sheath from the laser delivery device assembly after activating the laser light source at the first location. In some embodiments, the method can include withdrawing the probe to a second location within the first path within the tumor using a scale on the probe to measure the distance between the first location and the second location. In some embodiments, the method can include reconnecting the catheter sheath to the laser delivery device assembly with a sheath connector. In some embodiments, the method can include activating the laser light source when the introducer probe is at the second location to irradiate the tissue with sub-ablative infrared radiation for a second period of time. In some embodiments, the second location can be located proximal to the first location.

[0040] In some embodiments, the tumor can be a prostate tumor.

[0041] Some embodiments relate to a method of manufacturing a laser applicator assembly. In some embodiments, the method may include obtaining a body of the laser applicator assembly. In some embodiments, the method may include affixing a probe to the body. In some embodiments, the method may include affixing a sheath connector to the laser applicator assembly. In some embodiments, the sheath connector can be affixed to the body. In some embodiments, the sheath connector can be affixed to the probe. In some embodiments, the sheath connector can be disposed between the body and the probe.

[0042] In some embodiments, the laser illumination system may include a laser illuminator assembly. In some embodiments, the laser illuminator assembly may be provided as a stand-alone component, external to the laser illumination system, as disclosed elsewhere herein. In some embodiments, the laser illuminator assembly may include a sheath connector. In some embodiments, the laser illuminator system may include a trocar assembly. In some embodiments, the laser illuminator system may include a catheter sheath. In some embodiments, the laser illuminator system may include an optical fiber having a diffuser tip and a fiber optic connector. In some embodiments, the fiber optic connector may be configured to engage the laser illuminator assembly. In some embodiments, when the fiber optic connector is engaged with the laser illuminator assembly, the diffuser tip of the optical fiber may be disposed within the laser illuminator assembly. In some embodiments, the laser illumination system may include a laser light source configured in optical communication with the optical fiber. In some embodiments, the ablation may be configured to transmit radiation through the optical fiber to the laser illuminator assembly. In some embodiments, when activated, the ablation transmits electromagnetic radiation through the optical fiber and through the sealed end. In some embodiments, the laser illumination system may include a coolant reservoir. In some embodiments, the coolant reservoir may be in fluid communication with the laser illumination assembly. In some embodiments, the laser illuminator assembly can include a coolant inlet tube configured to deliver coolant from the coolant reservoir to the laser illuminator assembly. In some embodiments, the laser illumination system can include a pump configured to deliver coolant from the coolant reservoir through the coolant inlet tube to the laser illuminator assembly for cooling the optical fiber. In some embodiments, the laser illumination system can include a coolant collection bag in fluid communication with the laser illuminator assembly and configured to receive coolant from the laser illuminator assembly.In some embodiments, the laser applicator assembly can include a coolant outlet tube configured to transport coolant from the laser applicator assembly to a coolant collection bag. In some embodiments, the laser illumination system can include an actuator configured to activate and deactivate the laser light source. In some embodiments, the actuator can be a foot pedal. In some embodiments, the actuator also controls the pump. In some embodiments, the laser and the pump can be activated substantially simultaneously by the actuator. In some embodiments, the laser and the pump can be deactivated substantially simultaneously by the actuator. In some embodiments, the coolant inlet tube can be a Tygon material. In some embodiments, the length of the coolant inlet tube can be about 4 meters. In some embodiments, the coolant inlet tube can be configured to allow coolant flow at a low rate. In some embodiments, the coolant inlet tube can be configured to allow coolant flow at a rate of about 8 ml / min. In some embodiments, the ablation can be at a near infrared wavelength. In some embodiments, the ablation provides radiation having a wavelength in the range of about 805 nm to about 810 nm. In some embodiments, the optical fiber can include a diffusing section configured to distribute radiation from the optical fiber out of the laser irradiation device assembly. In some embodiments, the length of the diffusing section of the optical fiber ranges from about 1.0 cm to about 1.8 cm. In some embodiments, the length of the diffusing section of the optical fiber is about 50 mm, 30 mm, 18 mm, 10 mm, values ​​between the aforementioned values, or ranges including and / or spanning those values. [Brief description of the drawings]

[0043] The features of the laser projection device assembly, laser illumination system, and components thereof disclosed herein are described below with reference to drawings of specific embodiments. The illustrated embodiments are intended to illustrate, but not limit, the disclosure. The proportions and relative dimensions and sizes of each component shown in these drawings form part of the disclosure of this specification, but should not limit the scope of this specification, except to the extent that such proportions, dimensions or sizes are included in the individual claims.

[0044] [Figure 1] FIG. 1 illustrates one embodiment of a laser projection system. [Figure 2A] FIG. 2A illustrates an embodiment of a laser catheter assembly including a sheath connector. [Figure 2A-1] FIG. 2A-1 is an enlarged view of the laser catheter assembly shown in FIG. 2A. [Figure 2A-2] FIG. 2A-2 is an enlarged view of the laser catheter assembly shown in FIG. 2A. [Figure 2A-3] FIG. 2A-3 is an enlarged view of the laser catheter assembly shown in FIG. 2A. [Figure 2B] FIG. 2B is a perspective view of another embodiment of a laser catheter assembly in which the sheath connector is integrated into the body of the laser catheter assembly. [Figure 2C] FIG. 2C is an additional laser catheter assembly including a sheath connector. [Figure 2D] FIG. 2D is an additional laser catheter assembly including a sheath connector. [Figure 2E] FIG. 2E is an additional laser catheter assembly including a sheath connector. [Figure 3A] FIG. 3A illustrates an embodiment of an optical fiber that can be inserted into the laser catheter assembly of FIG. 2A. [Figure 3B] FIG. 3B is a perspective view of the optical fiber shown in FIG. 3A. [Figure 4] FIG. 4 illustrates one embodiment of a coolant inlet conduit. [Figure 5A] FIG. 5A illustrates one embodiment of a coolant collection bag. [Figure 5B] FIG. 5B is a perspective view of the coolant recovery bag shown in FIG. 5A. [Figure 6A] FIG. 6A is a diagram of a trocar sleeve assembly. [Figure 6A-1] FIG. 6A-1 is a diagram of a trocar sleeve assembly. [Figure 6A-2] FIG. 6A-2 is a diagram of a trocar sleeve assembly. [Figure 6A-3] FIG. 6A-3 is a diagram of a trocar sleeve assembly. [Figure 6A-4] FIG. 6A-4 is a diagram of a trocar sleeve assembly. [Figure 6B] FIG. 6B is a diagram of a trocar sleeve assembly. [Figure 6B-1] FIG. 6B-1 is a diagram of a trocar sleeve assembly. [Figure 6B-2] FIG. 6B-2 is a diagram of a trocar sleeve assembly. [Figure 6B-3] FIG. 6B-3 is a diagram of a trocar sleeve assembly. [Figure 6B-4] FIG. 6B-4 is a diagram of a trocar sleeve assembly. [Figure 7A] FIG. 7A illustrates the insertion and illumination of a test tissue using an embodiment of a laser catheter assembly described herein. [Figure 7B] FIG. 7B illustrates the insertion and illumination of a test tissue using an embodiment of a laser catheter assembly described herein. [Figure 7C] FIG. 7C illustrates the insertion and illumination of a test tissue using an embodiment of a laser catheter assembly described herein. [Figure 7D] FIG. 7D illustrates the insertion and illumination of a test tissue using an embodiment of a laser catheter assembly described herein. [Figure 7E]FIG. 7E illustrates the insertion and illumination of a test tissue using an embodiment of a laser catheter assembly described herein. [Figure 7F] FIG. 7F illustrates the insertion and illumination of a test tissue using an embodiment of a laser catheter assembly described herein. [Figure 7G] FIG. 7G illustrates the insertion and illumination of a test tissue using an embodiment of a laser catheter assembly described herein. [Figure 7H] FIG. 7H illustrates the insertion and illumination of a test tissue using an embodiment of a laser catheter assembly described herein. [Figure 7I] FIG. 7I illustrates the insertion and illumination of a test tissue using an embodiment of a laser catheter assembly described herein. [Figure 7J] FIG. 7J illustrates the insertion and illumination of a test tissue using an embodiment of a laser catheter assembly described herein. [Figure 7K] FIG. 7K illustrates the insertion and illumination of a test tissue using an embodiment of a laser catheter assembly described herein. [Figure 7L] FIG. 7L shows an embodiment of a probe tip that contains a waveguide. [Figure 8A] FIG. 8A illustrates an embodiment of a hexagonal grid template for laser probe placement. [Figure 8B] FIG. 8B illustrates an embodiment of a square grid template. [Figure 8C] FIG. 8C illustrates an embodiment of a laser exposure region using a hexagonal grid template with 7 mm spacing between grid openings. [Figure 8D] FIG. 8D shows an embodiment of a laser exposure region using a square grid template with 3 mm spacing between grid openings. [Figure 8E] FIG. 8E is an illustration of a decomposed 3-division square grid. [Figure 8F]FIG. 8F is a diagram of a monolithic hexagonal grid embodiment. [Figure 8G] FIG. 8G is a perspective view of an embodiment of a 3-division square grid. [Figure 9A] FIG. 9A illustrates components of one embodiment of a laser illumination system kit. [Figure 9B] FIG. 9B illustrates components of one embodiment of a laser illumination system kit. [Figure 9C] FIG. 9C illustrates components of one embodiment of a laser illumination system kit. [Figure 9D] FIG. 9D illustrates components of one embodiment of a laser illumination system kit. [Figure 9E] FIG. 9E illustrates components of one embodiment of a laser illumination system kit. [Figure 9F] FIG. 9F illustrates components of one embodiment of a laser illumination system kit. [Figure 9G] FIG. 9G illustrates components of one embodiment of a laser illumination system kit. [Figure 10A] FIG. 10A is a photograph of the experimental setup for testing the conical tip laser catheter and the transparent tip laser catheter assembly. [Figure 10B] FIG. 10B is a photograph of the experimental setup for testing the conical tip laser catheter and the transparent tip laser catheter assembly. [Figure 11A] FIG. 11A is a graph showing the heating of a conical tip laser catheter (11A) and a rounded transparent tip laser catheter assembly (11B). [Figure 11B] FIG. 11B is a graph showing the heating of a conical tip laser catheter (11A) and a rounded transparent tip laser catheter assembly (11B). [Figure 12A]FIG. 12A shows a thermal image of the distal end of a cone-tip laser catheter after 6.0 W irradiation. [Figure 12B] FIG. 12B shows a thermal image of the distal end of the cone-tip laser catheter after 6.0 W irradiation. [Figure 12C] FIG. 12C shows a thermal image of the distal end of the domed tip laser catheter after 6.0 W irradiation. [Figure 12D] FIG. 12D shows a thermal image of the distal end of the domed tip laser catheter after 6.0 W irradiation. [Figure 13] FIG. 13 shows the heating of a cone-tip laser catheter using an optical fiber with an 18 mm diffuser. [Figure 14A] FIG. 14A is a photograph of nine whole-mount sections of a patient's prostate (scale bar=1 cm). [Figure 14B] FIG. 14B is a photograph of nine whole-mount sections of the patient's prostate (scale bar=1 cm). [Figure 14C] FIG. 14C is a photograph of nine whole-mount sections of the patient's prostate (scale bar=1 cm). [Figure 14D] FIG. 14D is a photograph of nine whole-mount sections of a patient's prostate (scale bar=1 cm). [Figure 14E] FIG. 14E is a photograph of nine whole-mount sections of a patient's prostate (scale bar=1 cm). [Figure 14F] FIG. 14F is a photograph of nine whole-mount sections of a patient's prostate (scale bar=1 cm). [Figure 14G] FIG. 14G is a photograph of nine whole-mount sections of a patient's prostate (scale bar=1 cm). [Figure 14H] FIG. 14H is a photograph of nine whole-mount sections of the patient's prostate (scale bar=1 cm). [Figure 14I] FIG. 14I is a photograph of nine whole-mount sections of a patient's prostate (scale bar=1 cm). [Figure 15]FIG. 15 is a graph showing the relative accumulation of nanoparticles in tumor versus healthy tissues of samples from two patients. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0045] Some embodiments disclosed herein relate to methods of treating tumors (e.g., cancer tumors), systems used to irradiate tissues and tumors with electromagnetic radiation, components and devices of the systems, and kits for providing the systems used to irradiate tissues and tumors with electromagnetic radiation. In some embodiments, the systems may be configured to provide infrared radiation (e.g., to the patient's tissue). In some embodiments, the infrared radiation may be non-ablative radiation (e.g., radiation of insufficient intensity to ablate tissue by itself and / or sub-ablative radiation). In some embodiments, the non-ablative infrared radiation may be absorbed by nanoparticles that may be dispersed in or around the target tissue to be treated. In some embodiments, the nanoparticles absorb the radiation and convert it to thermal energy. In some embodiments, even though the infrared radiation itself is sub-ablative, the thermal energy generated by the nanoparticles may be sufficient to cause thermal coagulation, hyperthermia, and / or tissue ablation. Various methods, devices, systems, and kits for treating tumors and ablating tissue are described below to illustrate various examples that may be employed to achieve one or more desired improvements. These examples are illustrative only and are not intended to limit the general inventions presented and the various aspects and features of these inventions. Moreover, the words and terms used herein are for the purpose of explanation and should not be considered limiting. No feature, structure, or step disclosed herein may be essential or indispensable. Any of the systems or methods disclosed herein may exclude one or more steps or features described herein.

[0046] Photothermal coagulation as a treatment can take advantage of the ability of laser energy to be transmitted through optical fibers to deliver specific amounts of energy interstitially to tissue. Laser Interstitial Thermotherapy (LITT) is a technique that delivers enough optical power to cause thermal coagulation directly into tissue. Essentially, optical energy can be delivered to tissue at a rate greater than the body's ability to remove the resulting heat. This heat results in hyperthermia and tissue ablation.

[0047] However, the effective treatment depth of LITT and other photon-based therapies can be hindered by scattering and absorption of light in tissue (including by thermal coagulation). This scattering and absorption can result in light intensity that decreases exponentially with increasing distance from the light source into the tissue. A further limitation is that the light intensity, or irradiance (W / cm), when delivered by a one-dimensional light source (e.g., a fiber optic diffuser used to deliver laser light between tissues), can be very large. 2 The irradiance (measured at ) also decreases and / or declines radially. The net result is that the light irradiance may be higher in close proximity to the light source that irradiates it and much lower in areas outside the immediate vicinity of the light source (e.g., diffuser). The shape of the coagulation region may be a function of the geometry of the energy source, and the volume of the coagulation region may depend on the total energy deposited. For example, current laser catheters used for photon-based treatments use fiber optic diffusers and 12-15 W of power to generate an elliptical coagulation zone around the diffuser. As such, selectivity to the target tissue is low.

[0048] Additionally, current systems require high power irradiance, which can generate high laser temperatures and destroy and / or deform the laser delivery catheter. This also causes carbonization of the tissue, blocking the depth to which radiation can penetrate the tissue. Active cooling can be used to prevent carbonization of the tissue immediately after the laser delivery catheter and / or to prevent damage to the instrument. Nevertheless, even with cooling, many catheters have tips that absorb thermal energy and melt the laser catheter. It has also been noted that it can be difficult to accurately position the catheter probe in the tissue. This can lead to physicians roughly judging the location of the laser catheter in the tissue, which can result in some areas being undertreated and some areas being overtreated. Additionally, laser catheters are very fragile and can kink or break, which can cause treatment to be aborted and can also exacerbate the heating and charring problem. Some embodiments disclosed herein provide solutions to one or more of these problems or other problems.

[0049] In some embodiments, disclosed herein are methods, devices, systems, and kits configured to deliver radiation to generate photothermal coagulation. In some embodiments, disclosed herein are methods, devices, systems, and kits configured to deliver non-ablative radiation (e.g., using nanoparticles or other agents) to generate particle-directed photothermal coagulation. In some embodiments, the disclosed techniques and devices allow for improved selectivity in targeting tissue and effectively treating tissue. Some embodiments disclosed herein relate to systems and devices used to generate radiation at sites where photothermal coagulation, hyperthermia, and / or tissue ablation may be desired.

[0050] In some embodiments, the methods and devices relate to photothermal coagulation for use in treating tumors. In some embodiments, a laser probe of a laser catheter assembly may be positioned (e.g., inserted, placed, etc.) at or near a site of interest (e.g., within or near a tumor). In some embodiments, the laser catheter assembly may be operated to irradiate tissue with electromagnetic radiation (e.g., ultraviolet, visible, near infrared, far infrared, microwave, etc.). In some embodiments, the radiation may be infrared. In some embodiments, the laser catheter assembly delivers radiation that may be of sufficient intensity to cause photothermal coagulation (e.g., radiation that may be ablative radiation), hyperthermia, and / or tissue ablation.

[0051] In some embodiments, the methods and devices relate to particle-directed (e.g., nanoparticle-based) photothermal coagulation for use in the treatment of tumors. In some embodiments, the methods involve injecting nanoparticles into a patient having a tumor (or another tissue that can be targeted). In some embodiments, the nanoparticles are allowed to accumulate in the tumor over a defined period of time. In some embodiments, once the nanoparticles have accumulated at the site of interest, the laser probe of the laser catheter assembly can be positioned (e.g., inserted, placed, etc.) at or near the site of interest (e.g., in or near a tumor). In some embodiments, the laser catheter assembly can be actuated to irradiate the nanoparticles with electromagnetic radiation (e.g., ultraviolet, visible, near infrared, far infrared, microwave, etc.). In some embodiments, the radiation can be infrared radiation. In some embodiments, the laser catheter assembly delivers radiation that can be of insufficient intensity to cause photothermal coagulation (e.g., radiation that can be non-ablative and / or sub-ablative radiation), thermotherapy, and / or tissue ablation by itself (e.g., in the absence of nanoparticles). In some embodiments, the radiation intensity can be converted to thermal energy by the nanoparticles. In some embodiments, the heat transferred by the nanoparticles can be sufficient to cause ablative thermotherapy, tissue coagulation, and / or tissue ablation.

[0052] In some embodiments, the nanoparticles used in the disclosed methods can be designed to absorb infrared radiation and convert it to thermal energy. In some embodiments, gold nanoshells (e.g., AuroShell®, etc.) can be used as nanoparticles that convert sub-ablative infrared radiation to ablation temperatures. It should be noted that while gold nanoshells (e.g., AuroShell®, etc.) are used as representative nanoparticles for illustration purposes, any nanoparticle (or microparticle) that absorbs infrared photons and converts those photons to thermal energy can be envisioned. Without being bound to a particular theory, it can be believed that absorption of a photon by a nanoshell effectively annihilates the photon, converting its energy to heat and releasing it into the surrounding tissue. If the photon can be scattered (e.g., not absorbed) by the particle, the scattered photon is available for absorption elsewhere (e.g., tissue, another nanoshell, etc.). Permeable nanoparticles include, among others, nanoshells (including gold-shelled silica core nanoshells such as AuroShell®, gold-gold sulfide nanoshells, and other variations), solid nanospheres (gold, silver, etc.), metal nanorods (gold, silver, etc.), nanostars, hollow nanorods (gold, silver, etc.), metal nanorods (gold, silver, etc.), nanostars, hollow nanoparticles, nanocages, ellipsoidal "nanoliths," carbon particles, fullerenes, carbon fullerenes, metal nanoparticles, metal colloids, carbon particles, carbon nanotubes, buckyballs, and any combination thereof.

[0053] In some embodiments, the methods disclosed herein can be used to target tissue for treatment. In some embodiments, the target tissue can be tumor tissue. In some embodiments, the tumor target includes tumors caused by cancer. In some embodiments, the tumor can be tumors caused by colorectal cancer, brain cancer, lung cancer, breast cancer, head and neck cancer, pancreatic cancer, ovarian cancer, melanoma cancer, prostate cancer, and other forms of cancer. In some embodiments, the techniques disclosed herein can be suitable for treating tumors in tissues and / or for maintaining healthy tissue function while destroying the underlying tumor tissue. For example, in some embodiments, the techniques and devices disclosed herein can be used to specifically target tumor tissue or dysfunctional tissue. Loss of function of certain healthy tissues can have devastating effects on a patient's quality of life. For example, surgical procedures to remove cancer tumor tissue from the pharynx can cause dysphonia. Surgical procedures to resect cancer tumor tissue from the prostate can cause loss of sexual function. Current resection methods can heat tissue based on placing a heating instrument within the tumor. Activation of the heating tool can kill surrounding tissue, including healthy tissue. In some embodiments, the therapeutic methods disclosed herein can partially, substantially, and / or completely preserve the structure and / or function of underlying non-diseased healthy tissue to promote or substantially maintain normal function of the underlying tissue.

[0054] In some embodiments, the method includes injecting (e.g., infusing) the nanoparticles systemically into the patient. Systemic introduction can include introduction of the nanoparticles into the circulatory system and / or introduction of the nanoparticles into a site in the body that is distant from the target site. In some embodiments, the nanoparticles can be introduced into the patient via a parenteral route of administration (e.g., intravenous, intramuscular, subcutaneous, intracavitary, intraperitoneal, etc.). These sites can be located at sites in the patient's body that are not in close proximity to the treatment site (e.g., sites in the body other than the tumor site). For example, the nanoparticles preferentially accumulate primarily in tumors as a result of their size and passive exfiltration from the leaky, chaotic, and immature vasculature of tumors. In some embodiments, this passive accumulation allows targeted deposition of the radiation converter, allowing tumor-specific photothermal coagulation therapy.

[0055] In some embodiments, the nanoparticles can be passively accumulated in the tumor after being introduced into the body. In some embodiments, this passive accumulation can be achieved by the passage of a defined period of time. In some embodiments, the nanoparticles can be accumulated in the tumor for a period equal to or at least about 12 hours and / or equal to or less than about 36 hours after infusion and / or injection. In some embodiments, the nanoparticles can be accumulated at the tumor site for a period of at least about 12 hours, about 24 hours, about 36 hours, or a range including and / or spanning the aforementioned values.

[0056] In some embodiments, the nanoparticles accumulate in the perivascular spaces of tumor neovasculature and act as foci for laser energy. In some embodiments, after accumulating at the site of interest, the nanoparticles can be heated using laser energy and / or electromagnetic energy. In some embodiments, the laser energy (e.g., electromagnetic energy) heats the nanoparticles to a temperature sufficient to cause thermocoagulation, hyperthermia, and / or ablation of the target tissue.

[0057] In some embodiments, as shown in FIG. 1, a laser delivery system 100 can be used to generate laser energy at a target site for treatment. In some embodiments, as shown in FIG. 1, the laser delivery system 100 can include a laser catheter assembly 101 (e.g., a laser illuminator). Although not shown in FIG. 1, the system can further include a catheter sheath 426 (as shown in FIGS. 6A-6A-4). Although not shown in FIG. 1, in some embodiments, the system can include a trocar 425 (as shown in FIGS. 6A-6A-4). Although not shown in FIG. 1, the system can further include a trocar assembly 400 (as shown in FIGS. 6A-6A-4), which can include a trocar 425 and a catheter sheath 426.

[0058] In some embodiments, the laser illumination system may further include one or more of an illumination system 200 and a cooling system 300, as shown in FIG. 1. In some embodiments, the illumination system 200 may include an optical fiber 202 and / or a laser light source 203. In some embodiments, the optical fiber 202 may be configured to connect to, be in optical communication with, and / or receive laser energy from the ablation 203. In some embodiments, the ablation, the optical fiber, and / or the laser catheter may be in optical communication, as disclosed elsewhere herein. In some embodiments, the cooling system may include one or more of a coolant reservoir 305, a coolant pump 307, and / or a coolant collection bag 309. In some embodiments, the coolant reservoir, the laser catheter assembly, and / or the coolant collection bag may be configured to be in fluid communication with one another, as disclosed elsewhere herein.

[0059] In some embodiments, the laser illumination system includes the laser catheter assembly 1101 but lacks one or more other features, such as the illumination system 200 and / or the coolant supply system 300 and / or any of the individual components described above.

[0060] As shown in FIG. 1, in some embodiments, the laser illuminator 101 can include a body 102, hubs 106, 109, 120a configured to engage various features of the laser illumination system (e.g., cooling fluid conduits, fiber optic connectors, etc.), a probe 113 (e.g., an introducer probe configured to be inserted into a patient's body and / or tissue), and a sheath connector 150.

[0061] As shown in Figure 1 and disclosed elsewhere herein, in some embodiments, the laser catheter assembly 101 can include one or more hubs 106, 109, 120a. As shown in Figure 2, these hubs 106, 109, 120a can be located on and / or in portions of the body 102 of the laser applicator assembly 101. In some embodiments, the hubs can include connection structures configured to engage various connectors, as disclosed elsewhere herein.

[0062] In some embodiments, as shown in FIG. 1, the body 102 of the laser catheter assembly 101 can be configured to receive coolant via a hub 106. In some embodiments, the hub 106 can include a coolant inlet connector (not shown) or the hub 106 can be configured to engage a coolant inlet connector assembly having an inlet connector 104 (as shown in FIG. 2A). As shown in FIG. 2B, the coolant inlet connector 104 can be in fluid communication with the body via a catheter conduit connector 104a of the hub 106 and a catheter conduit 132 having a hub mating connector 106a. In some embodiments, the coolant inlet connector assembly can include the coolant inlet connector 104, the catheter conduit 132, and the catheter conduit connector 104a. In some embodiments, the catheter conduit connector 104a and the hub mating connector 106a can include various connection structures as disclosed elsewhere herein.

[0063] In some embodiments, the hub 106 may include a connection structure and / or connector configured to directly engage a corresponding inlet conduit connector 310 of the coolant inlet conduit 306 (not shown). For example, in some embodiments, the laser delivery device assembly may lack an intervening catheter inlet conduit 132 and separate coolant inlet connector 104.

[0064] In some embodiments, the hub 106 may include a port that provides an access point to the body 102 of the laser illuminator 101. For example, in some embodiments, the laser illumination system 100 may include a coolant reservoir 305 (e.g., a bag, a bottle, etc.). In some embodiments, when connected to the laser illumination assembly 101, the coolant reservoir 305 may be in fluid communication with the coolant inlet connector 104 via a coolant inlet conduit 306. In some embodiments, upon operation, coolant from the coolant reservoir 305 may be transported through the coolant inlet connector 104 and the hub 106 into the laser catheter assembly 101 via operation of the coolant pump 307. In some embodiments, the coolant inlet conduit 306 has an inlet conduit connector 310 that may be configured to interface with the coolant inlet connector 104.

[0065] In some embodiments, as shown in FIG. 1, the body 102 of the laser catheter assembly 101 can be configured to exit the coolant through an outlet hub 109. In some embodiments, the hub 109 (e.g., an outlet hub) can include a coolant outlet (not shown). The coolant outlet connector 108 may include, or may be configured to engage (as shown in FIG. 2B ) a coolant outlet assembly having a coolant outlet connector 108. As shown in FIG. 2B , the coolant outlet connector 108 may be in fluid communication with the body 102 via a catheter conduit 127 having a catheter conduit connector 108a and a hub mating connector 109a of the hub 109. In some embodiments, the coolant outlet connector assembly may include the coolant outlet connector 108, the catheter conduit 127, and the catheter conduit connector 108a. In some embodiments, the catheter conduit connector 108a and the hub mating connector 109a may include various connection structures as disclosed elsewhere herein.

[0066] In some embodiments, the hub 109 can include a connection structure and / or connector configured to directly engage with a corresponding outlet conduit connector 324 of the coolant outlet conduit 311 (not shown). For example, in some embodiments, the laser delivery device assembly can lack the intervening catheter outlet conduit 127 and separate coolant outlet connector 108.

[0067] In some embodiments, the laser delivery system 100 can include a coolant collection bag 309 (e.g., a bag, bottle, etc.). In some embodiments, the coolant collection bag 309 can be in fluid communication with the coolant outlet connector 108 via a coolant outlet conduit 311. In some embodiments, during operation, coolant from the laser catheter assembly 101 can be transferred to the coolant collection bag 309 via the coolant outlet connector 108. In some embodiments, the coolant outlet conduit 311 has an outlet conduit connector 312 that can be configured to interface with the coolant outlet connector 108.

[0068] 2A, the inlet and outlet connectors 104, 108 of the laser catheter assembly 101 may be of different genders. In some embodiments, this configuration can prevent incorrect and / or mismatched connection of the inlet and outlet connectors of the laser catheter assembly 101 to the coolant supply and recovery attachments (e.g., prevent reverse connection). For example, as shown in FIG. 1 , the coolant inlet connector 104 can be a female connector having a female receptacle 104′, the coolant supply inlet 310 can have a male protrusion 315 and optionally a shroud 316 (e.g., the coolant outlet connector 108 can be a male connector having a male protrusion 108′ and optionally a shroud 108″ (e.g., a hood, a threaded shroud, etc.), and the coolant outlet conduit connector 324 can have a female connection with a female receptacle 325. In some embodiments, the coolant inlet connector 104 can be a male connector, while the coolant outlet connector 108 can be a female connector (not shown). In some embodiments, instead of or in addition to having different genders, the inlet connector 104 and the outlet connector 108 can be , may be color coded to match the color of the inlet conduit connector 310 and the outlet conduit connector 324 (not shown). For example, in some embodiments, the inlet connector 104 and the inlet conduit connector 310 may be one color (e.g., red, orange, yellow, green, cyan, blue, indigo, purple, violet, magenta, pink, brown, white, and the outlet connector 108 and the outlet conduit connector 324 may be another different color (e.g., red, orange, yellow, green, cyan, blue, indigo, purple, violet, magenta, pink, brown, white, gray, black). In some embodiments, the male and female connectors may be luer connectors (which in some embodiments may include an ISO 594 compliant luer taper). In some embodiments, the inlet and outlet connectors may not be of different genders, if desired.

[0069] In some embodiments, the laser applicator assembly can include a sheath connector 150 configured to mate with a corresponding connector (e.g., its mate). In some embodiments, the mating of the sheath connector 150 may be a connector of the catheter sheath 440. In some embodiments, the sheath connector 150 may include a connecting structure and the connector of the catheter sheath 440 may include a corresponding connecting structure. In some embodiments, when the sheath connector 150 is engaged with the connector of the catheter sheath 440, the catheter sheath 426 may be configured to at least partially cover the probe 113. As shown in FIGS. 2A-2E, the sheath fitting 150 (e.g., the sheath connector) may be at least partially disposed circumferentially around at least a portion of the elongated probe member. In other embodiments not shown, the sheath fitting is optionally not disposed circumferentially around the probe. For example, the sheath connector may be a hinge that engages teeth or lips of the catheter sheath (not shown). In some embodiments, the sheath fitting may be connected to and / or integral with the body of the laser irradiation device assembly. For example, the sheath fitting may be welded to, molded into, or integral with the laser illuminator body. In other embodiments, the sheath connector may be connected to and / or integral with the elongated probe member. For example, the sheath connector may be welded to, molded into, or integral with the probe of the laser illuminator.

[0070] In some embodiments, as disclosed elsewhere herein, the sheath connector 150 and / or other connectors disclosed herein (such as fluid inlet and outlet connectors, waveguide / fiber optic connectors, trocar connectors, connectors of catheter sheaths, corresponding mating connectors of any of the foregoing, etc.) can include one or more connecting structures. These connecting structures can include one or more ridges, threads, catches, arms, latches, protrusions, recesses, or combinations of any of the foregoing. The connecting structures can include tapers (e.g., configured to engage with corresponding tapers of their mating connectors).

[0071] In some embodiments, the connecting structure of the first connector (e.g., sheath connector 150) may be configured to help guide, attach, and / or hold a corresponding connector (e.g., a connector of the catheter sheath 440) in an engaged state for mating with the corresponding connector. In some embodiments, the first connector (e.g., sheath connector 150) engages (e.g., provides a friction fit) with a corresponding connector (e.g., a connector of the catheter sheath 440) via friction. In some embodiments, the connecting structure may include threads. In some embodiments, at least a portion of the threads may be oversized. In some embodiments, the threads may include cut-resistant features (e.g., locking features, barbs, threads that expand the more the connectors are twisted together, etc.). In some embodiments, the anti-disconnect feature requires an initial force to overcome the retention of the anti-disconnect feature and another smaller force thereafter to disconnect the connectors after they are engaged with their counterparts.

[0072] In some embodiments, the mating pair of connectors (e.g., the connector mating, such as the sheath connector 150 and the catheter sheath 440 connector) may be male and female Luer connectors (e.g., may include connection structures that may be male and female components of a Luer connector, respectively). In some embodiments, the connectors may include ISO 594 compliant Luer tapers. For example, the catheter sheath 440 connector may be a female connector with a female receiver, and the sheath connector 150 may have a male connection with a male protrusion (which may provide a portion of the probe 113 or transition directly from the probe 113). In some embodiments, as shown in FIG. 2A, the sheath connector may optionally include a shroud 151 (e.g., a hood, a threaded shroud, etc.), and the catheter sheath 440 connector may have a female connection with a female receiver 441.

[0073] 2A and 2B, in some embodiments, the laser catheter assembly 101 can include an introducer probe 113. In some embodiments, as shown in FIG. 2A, the laser catheter assembly 101 can include one or more of an outlet arm unit 125, an outlet arm 126, and an inlet arm unit 130, and an inlet arm 131. In some embodiments, the introducer probe 113 can include an elongated tube (e.g., an elongated probe member) extending from a proximal introducer probe connector seal 135 (e.g., a seal, sleeve, etc.) to a sealed end 115 of the introducer probe 113.

[0074] In some embodiments, the introducer probe 113 can include an outer tubular portion 114 (e.g., an outer wall that defines a tubular cavity within the introducer probe). In some embodiments, as shown in Figures 2A and 2B, the outer tubular portion 114 can be a continuous material (e.g., a single piece molded from a single material, a monolithic structure, etc.). In some embodiments, the outer tubular portion 114 can be transparent or substantially transparent to certain wavelengths of electromagnetic radiation, such as, for example, one or more of ultraviolet, visible, near infrared, far infrared, and / or microwave radiation.

[0075] In some embodiments, the outer tubular portion 114 can include a sealed end 115. In some embodiments, the sealed end 115 can be transparent, optically and / or infrared transparent, and / or substantially optically and / or infrared transparent. In some embodiments, the sealed end 115 can be transparent or substantially transparent to certain wavelengths of electromagnetic radiation, such as one or more of ultraviolet, visible, near infrared, far infrared, and / or microwave radiation. In some embodiments, the sealed end 115 can be transmissive. In some embodiments, the sealed end 115 allows electromagnetic radiation from the ablation 203 to pass therethrough (e.g., via a diffuser tip 204 as disclosed elsewhere herein). 2A-2, the sealed end 115 can be shaped to distribute light from the optical fiber 202 in a conical distribution 140 that expands outward and distally from the sealed end 115 in line with the introducer probe 113, or in a hemispherical distribution 141 that expands outward and distally from the sealed end 115. In some embodiments, the distribution of light (conical or hemispherical) can be diffused such that the amount of radiation at a given distance within the distribution can be substantially or approximately the same intensity (e.g., at points 140A and 140B, and / or at points 141C and 141D). In some embodiments, the end 115 can be configured to allow radiation and / or light to pass through without substantial absorption.

[0076] In some embodiments, the fiber optic tip 204 may be configured to inhibit the passage of radiation through the tip and / or the fiber optic tip 204 substantially blocks radiation. In some embodiments, the diffuser tip 223 may be configured to emit most and / or substantially all and / or all of the radiation received via the radiation source laterally (e.g., laterally from the diffuser tip) and not along the path of the optical fiber 202 (e.g., through the fiber optic tip 204). In some embodiments, a diffuser tip that emits radiation laterally (e.g., to the side) advantageously enables treatment of tissue adjacent to the diffuser tip 223. In some embodiments, this configuration prevents and / or reduces the amount of heating and / or irradiation of tissue immediately prior to the fiber tip 204.

[0077] In some embodiments, as described elsewhere herein, the diffuser tip 223 (e.g., of the waveguide) may be connected to a laser (e.g., the waveguide may be connected to a laser via a fiber optic connector 222). The introducer probe 113 may be configured to distribute electromagnetic radiation laterally from the introducer probe (when engaged with the laser irradiator assembly). In some embodiments, the intensity of electromagnetic radiation from the diffuser may be approximately equal or substantially equal at equal distances from the diffuser tip 223. In some embodiments, the light emitted from the introducer probe 113 may be dispersed and / or unfocused. In some embodiments, the light emitted from the introducer probe 113 may be substantially evenly distributed. In some embodiments, the light may be distributed from the diffuser along a surface of the diffuser such that the emitted radiation does not create shadows (e.g., where the radiation may be blocked by components of the laser catheter, etc.) and / or focusing. In some embodiments, the laser catheter assembly and / or the diffuser tip lack a focusing lens and do not include a mirror.

[0078] In some embodiments, the sealed end can be dome-shaped (e.g., hemispherical, hemispherically shaped, hemispherical, dome-shaped, etc.). In some embodiments, as described elsewhere herein, the sealed end can be transparent. In some embodiments, transparent means passing all, substantially all, or a portion of the electromagnetic radiation from the diffuser tip 223. In some embodiments, the outer tubular portion 114 can be continuous with the sealed end 115 (e.g., the sealed end and the outer tubular portion can be a single piece molded from a single material, a one-piece structure, etc.). In some embodiments, the transparent sealed end 115 has the advantage of reducing heat buildup at the tip of the probe. This feature helps to avoid melting of the probe and also allows for distribution of the laser to the tissue along the direction of the probe. In some embodiments, the sealed end can optionally be non-conical and / or non-ground material (e.g., scattering material, opaque or substantially opaque material, etc.). In some embodiments, it has been found that circular and / or conical configurations do not allow radiation to pass through the introducer probe. In some embodiments, it has been found that circular and / or conical configurations can concentrate radiation causing hot spots and heating that can lead to warping and / or scorching of the probe and / or burning of the tissue surrounding the probe.

[0079] In some embodiments, the domed tip can be made using radio frequency. In some embodiments, the domed tip can be formed from a nylon extrusion, which can be placed on a mandrel and then inserted into a stainless steel die. In some embodiments, the die can be heated with RF energy while a pneumatically actuated gripper can be used to simultaneously force the extrusion into the cavity and reflow / reshape the tip of the extrusion onto the end of the mandrel. In some embodiments, the RF machine can provide temperature, pressure, and time settings specific to the extrusion, allowing for very repeatable tips. In some embodiments, the tip can be optionally non-hemispherical, but of another shape that allows for the passage of radiation without substantial accumulation of heat or concentration of radiation (e.g., rounded cube end, cube end, rounded cylindrical end, cylindrical end, etc.).

[0080] In some embodiments, as shown in FIG. 2A-1, the outer tubular portion 114 can include a lumen 116 (e.g., a first lumen). In some embodiments, an inner tube 117 (e.g., an inner tubular member) resides within the first lumen 116. In some embodiments, the inner tube 117 can include a second lumen 118. In some embodiments, as shown in FIG. 2A and FIG. 2B, the laser catheter assembly 101 can be configured to receive coolant via the coolant inlet connector 104, through the catheter inlet conduit 132, through the inlet arm unit 131, and into the body of the inlet arm unit 130 that provides the fluid chamber 103b. The coolant is then passed through the inner tube 117 to the open pool 119, and into the second lumen 118. The fluid may flow through the first lumen 116, into another fluid chamber 103a, through the outlet arm unit 125, through the outlet arm 126, into the catheter outlet conduit 127, and out through the coolant outlet connector 108. In other words, in some embodiments, one or more of the coolant inlet connector 104, the catheter inlet conduit 132, the inlet arm unit 131, the inlet arm unit 130, the inner tube 117, the open pool 119, the first lumen 116, the outlet arm unit 125, the outlet arm 126, the catheter outlet conduit 127, and / or the coolant outlet connector 108 may be in fluid communication. In other embodiments not shown, the laser applicator assembly lacks one or more of the catheter inlet conduit, the inlet arm unit, the outlet arm, and the catheter outlet conduit. For example, the hubs 106, 109 may be located directly in the body 102 (not shown) of the laser applicator assembly 101.

[0081] In some embodiments, the introducer probe 113 extends from a proximal end to a distal end, with the sealed domed end 115 of the outer tubular portion 114 located at the distal end. In some embodiments, the inner tube 117 terminates a distance away from the sealed domed end 115, leaving an open pool 119 at the distal end of the introducer probe 113. In some embodiments, when an optical fiber may be disposed within the introducer probe 113, the end of the diffuser tip 223 terminates at or near the distal end of the inner tube 117. In some embodiments, a portion of the diffuser tip 223 protrudes from the inner tube 117 within the open pool 119. In some embodiments, this protrusion allows a more concentrated amount of electromagnetic radiation to penetrate the sealed end 115 of the introducer probe 113. In some embodiments, the open pool provides an area around which coolant can flow without substantial restriction by the fiber tip 204 (e.g., blocking and / or restricting the flow of coolant within the lumen).

[0082] In some embodiments, the laser catheter assembly 101 can include a waveguide hub 120a. In some embodiments, the waveguide hub 120a can include an opening 120 (e.g., an end opening). In some embodiments, the waveguide hub 120a can include a connection feature 120b configured to engage with a waveguide connector 222. In some embodiments, the laser catheter assembly 101 can be configured to receive the optical fiber 202 into the introducer probe 113 via the end opening 120. In some embodiments, the inner tube 117 can be configured to receive the optical fiber 202 into the second lumen 118. In some embodiments, the optical fiber connector 222 mates with a feature on the end opening 120 to provide a fluid-tight seal (e.g., the waveguide hub can include a connector having one or more connection structures). In some embodiments, the coupling fixes the diffuser tip 223 in position within the introducer probe 113. In some embodiments, the laser catheter assembly 101 can accommodate only one optical fiber 202, and the introducer probe 113 and inner tube 117 can be sized and / or configured to accommodate only one optical fiber tip 204 and / or diffuser tip 223.

[0083] In some embodiments, the second lumen 118 can be in fluid communication with the coolant inlet connector 104, as described elsewhere herein. In some embodiments, the first lumen 116 can be in fluid communication with the coolant outlet connector 108, as described elsewhere herein. In some embodiments, when the optical fiber 202 is disposed within the second lumen 118, the laser catheter assembly can be configured to allow passage of coolant from the coolant inlet connector 104, through the second lumen 118, to the first lumen 116, and out the coolant outlet connector 312.

[0084] In some embodiments, the lumen of the introducer probe 113 of the laser catheter assembly 101 can be formed from a material such as nylon, PA12 nylon, or similar materials. In some embodiments, PA12 nylon, as opposed to a material such as polycarbonate, advantageously provides lubricity for the introducer probe 113 to pass through the introducer and through tissue.

[0085] In some embodiments, as shown in FIG. 2A, the introducer probe 113 can include printed "hash" marks 121. In some embodiments, the introducer probe 113 can be graduated (e.g., by numbering, lettering, etc.). In some embodiments, the hash marks and / or graduations can clearly mark the penetration depth of the probe into the tissue (and / or the distance the probe is withdrawn from the tissue). As disclosed elsewhere herein, in some embodiments, the hash marks (e.g., graduations) can be located on the proximal portion of the probe. In some embodiments, the hash marks can optionally not be located on the distal portion of the probe. For example, in some embodiments, the hash marks can extend about 1 / 5 or less of the distal portion of the probe: the lower 1 / 5 of the probe, the lower 1 / 4 of the probe, the lower 1 / 3 of the probe, the lower 1 / 2 of the probe, or a range including and / or spanning these values. In some embodiments, the hash marks may be spaced at intervals equal to or less than about 4 mm apart, about 8 mm apart, about 12 mm apart, values ​​between or ranging from and / or including the aforementioned values. In some embodiments, the alternating hash marks and dots allow the laser catheter assembly 101 to be pulled back through the tissue for multiple treatments with various light diffusers (e.g., 1 cm diffuser, 1.8 cm diffuser, etc.), as discussed elsewhere herein. In some embodiments, these graduations and / or hash marks allow the user to directly visualize the depth of the probe. In some embodiments, these graduations and / or hash marks allow fine control of the position of the probe to allow for effective and / or controlled ablation of tissue. In some embodiments, the entire length or substantially the entire length of the probe may be graduated.In some embodiments, the introducer probe can be about 50 cm, 30 cm, 20 cm or less in length: 50 cm, 30 cm, 20 cm, 10 cm, values ​​between the aforementioned values, or ranges including and / or spanning those values.

[0086] In some embodiments, the optical fiber 202 can include a diffuser tip, as disclosed elsewhere herein. In some embodiments, the diffuser tip 223 can be a portion of the optical fiber 202 having radiation scattering features (e.g., topography, bumps, roughening, dimples, etc.) that encourage and / or allow radiation (e.g., laser light, photons, radiation) to exit the optical tip in different directions (e.g., scattering, diffusion, etc.). In some embodiments, these features can be provided as a gradient along the diffuser, with a lower density closer to the laser source 203 and a higher density further from the laser source 203. In some embodiments, the density gradient encourages a substantially uniform distribution of radiation along the entire diffuser tip. In some embodiments, the diffusing portion 223 of the optical fiber 202 can be of different lengths. In some embodiments, the diffusing portion of the optical fiber may be about 50 mm, 30 mm, 18 mm or less in length: 50 mm, 30 mm, 18 mm, 10 mm, values ​​between or including and / or spanning the aforementioned values. In some embodiments, a longer diffuser allows for the treatment of a larger tumor volume in the same amount of time by using more laser power and distributing it along the longer diffuser. In some embodiments, by using a smaller diffusing tip, less laser power can be used, allowing smaller sized tumors to be treated with greater specificity. In some embodiments, diffusers of various sizes can be used in a single treatment to tailor the treatment to specific areas of the body and specific tumor dimensions. In some embodiments, the optical fiber can be pliable and / or flexible and configured to move within the introducer probe without kinking or cracking, as shown in FIG. 3B. In some embodiments, the optical fiber has a length sufficient to position the laser source out of the way during surgery. In some embodiments, the length of the optical fiber can be less than or equal to 1 m, 2 m, 3 m, 5 m, or a range including and / or spanning the aforementioned values.

[0087] The following exemplary figures are provided to illustrate one or more improvements achieved with the disclosed design features of the laser catheter assembly. In some embodiments, hash marks located along the introducer probe allow the user to determine the location of the laser catheter diffuser tip and the extent of treatment to the tumor being targeted. In some embodiments, the initial positioning of the introducer probe (e.g., the depth of insertion into the body along the z-axis, and the lateral positioning along the x- and y-axes) can be determined using computed tomography. Once the initial position is reached, the hash marks can be used to pinpoint the treatment location. The probe can be withdrawn from one position to the next at intervals determined by the scale on the probe. The markings on the laser catheter assembly provide a "depth gauge" for the user to know how far the laser catheter assembly has penetrated the tissue or how far the probe has been withdrawn from the starting position. In some embodiments, for example, 8 mm spacing between hash marks and 8 mm spacing between intermediate "dots" between hash marks provide a 4 mm spaced "ruler" that allows for precise "pullback." As described elsewhere herein, in some embodiments, a grid can be used to aid in proper lateral positioning of the diffuser tip of the laser catheter assembly within the tissue. As disclosed elsewhere herein, in some embodiments, a pullback of 8 mm can be used with a grid allowance of 10 mm. These markings can provide a user with a straightforward way to know how deep the laser catheter can be positioned within the target tumor or tissue, and can also provide a straightforward means of incrementally pulling back the catheter to create a continuous ablation zone along the catheter trajectory.

[0088] In some embodiments, the optical fiber may include a fiber optic connector 122, as shown in Figures 3A and 3B. In some embodiments, the fiber optic connector (or waveguide connector) may include one or more connection structures configured to engage with corresponding structures of the waveguide hub 120a of the laser applicator assembly. For example, the waveguide connector 122 may include a luer connector, and in some embodiments, an ISO 594 compliant luer taper. In some embodiments, the fiber optic connector may be coupled at a fixed distance from the distal end of the fiber optic tip 204. In some embodiments, the fiber optic connector 122 may be configured to engage with the end opening 120 of the laser catheter assembly 101, as disclosed elsewhere herein. In some embodiments, a fixed positioning of the fiber optic connector 122 may ensure a proper setback of the diffuser tip within the laser catheter assembly 101. In some embodiments, fixing the optical fiber 202 within the laser catheter assembly 101 may help prevent tip melting and ensure proper coolant flow around the diffuser. In some embodiments, fixing the optical fiber can prevent the diffuser tip from slipping out of the laser catheter assembly 101. In some embodiments, fixing the optical fiber 202 within the laser catheter assembly 101 helps ensure that the laser properly diffuses out of the diffuser tip (e.g., if part of the diffuser is inwardly diffused). (For example, by preventing the diffuser from exiting the outer tube 117 or by preventing the diffuser from bottoming out against the probe 113 tip, which could occlude the flow of coolant and / or cause uneven distribution of emitted light.) In some embodiments, fixing the fiber can also advantageously provide sufficient diffusion of light from the tip of the introducer probe 113 to allow treatment of tissue in front of the tip (in addition to tissue laterally adjacent to the diffuser tip).

[0089] In some embodiments, the optical fiber has a total length in meters of 2, 3.5, 5, or less than or equal to a range including and / or spanning the aforementioned values. This length advantageously reduces clutter within an operating room, given that in some embodiments, an entire laser delivery system as disclosed herein can be sized to allow for being fully contained within an operating room (e.g., a sterile environment).

[0090] In some embodiments, the coolant supply system of the laser delivery system 100 may include a coolant reservoir 305, a coolant inlet conduit 306, and a coolant pump 307. In some embodiments, the coolant supply system supplies a coolant (e.g., saline, water, etc.) to the laser catheter assembly 101. In some embodiments, the coolant serves to prevent premature onset of photocoagulation adjacent the introducer probe 113 of the laser catheter assembly 101. Premature onset of photocoagulation can detrimentally limit optical penetration of the laser radiation to tissue and / or negate the tumor specificity of the optically excited nanoparticles.

[0091] FIG. 4 illustrates an embodiment of the coolant inlet conduit 306. In some embodiments, the length of the coolant inlet conduit 306 can be less than or equal to about 3 m, about 4 m, about 5 m, about 10 m, values ​​between the aforementioned values, or ranges spanning and / or including those values. In some embodiments, the length of the coolant inlet conduit 306 reduces clutter in an operational setup. In some embodiments, the coolant inlet conduit 306 can be constructed of flexible Tygon tubing (e.g., flexible tubing, such as polyvinyl chloride tubing) that allows it to be clamped to a coolant pump at any position along its length. In some embodiments, the diameter of the tubing can be about 1 / 8 inch. In some embodiments, the diameter of the tubing is about 1 / 12", 1 / 8", 1 / 4", or a range inclusive and / or spanning the aforementioned values. In some embodiments, this diameter allows for smaller pump head spacing, greater control of the coolant flow rate, and / or greater consistency of flow rate between tubing sets. In some embodiments, this feature eliminates the need for an external flow restrictor and meter in the return line. In some embodiments, this feature allows for more precise control of the coolant flow rate at low flow rates (e.g., about 8 mL / min or less) used during certain methods described herein. In some embodiments, the flow rate in mL / min that can be achieved can be 2, 4, 8, 10 or less, or a range including and / or spanning the aforementioned values. Figures 5A and 5B show one embodiment of a coolant collection bag. As shown in Figure 5B, the coolant collection bag can include a flexible length of tubing configured to attach to the laser catheter assembly.

[0092] In some embodiments, the design of the coolant supply set disclosed herein advantageously eliminates or reduces the problem of not being able to position the coolant pump relative to the reservoir that supplies the coolant. In some embodiments, the coolant supply system can be made of a continuous length of tubing, thereby reducing part count and complexity. In some embodiments, low flow rates (e.g., 8 mL / min) of coolant flow can be advantageously controlled by using polyvinyl chloride tubing with the inner diameter disclosed herein.

[0093] In some embodiments, the coolant pump 307 has a flow regulator that can be calibrated to initially set to a predetermined speed to generate a predetermined flow rate. In some embodiments, the pump can be a peristaltic pump (e.g., Langer BT100-1L). In some embodiments, the pump delivers a flow rate (mL / min) of about 0.002, 0.01, 0.1, 1, 20, 50, 100, 500 or less, or a range including and / or spanning the aforementioned values. In some embodiments, the coolant pump 307 has a quiet operation feature and operates at a decibel level of about 10, 20, 30, 40, 500 or less: 10, 20, 30, 40, 50, 60, 70, 80, or a range including and / or spanning the aforementioned values. In some embodiments, the quiet feature of the pump can be beneficial since the disclosed system can be placed in an operating room with the patient.

[0094] In some embodiments, the pump 307 can be connected to an actuation device (e.g., a foot switch, pedal, panel, button). In some embodiments, the actuation device can be turned on or off by a user (e.g., a physician or technician operating the pump). In some embodiments, the ablation can be connected to an actuation device (e.g., a foot switch, pedal, panel, button) that can be the same or different from the actuation device that controls the pump. In some embodiments where the pump and ablation actuation devices can be the same, the actuation device can have one or more toggle switches (e.g., buttons or panels) that allow the user to control the flow of coolant through the laser catheter and / or control the emission of the laser by the ablation separately or simultaneously. In some embodiments where the ablation and pump are actuated simultaneously, the actuation device can have a single switch for turning both the ablation and pump on or off simultaneously. In some embodiments where the ablation and pump are actuated separately, the actuation device can have different switches for actuating one device at a time.

[0095] In some embodiments, the actuator connection can allow coolant flow when the laser is active and stop the flow of coolant when it is inactive. In some embodiments, in addition to reducing the volume of coolant consumed (e.g., the number of coolant bag changes, etc.), this feature can advantageously prevent pre-cooling of tissue between laser treatments. In some embodiments, the pump can be programmable to have a pre-defined flow rate when the laser is operating. In some embodiments, control of the pre-defined flow rate of the pump can be useful for the disclosed methods that can use nominal sub-ablative laser doses without using real-time temperature monitoring. In some embodiments, the pre-defined flow rate in mL / min can be about or less than: 0.002, 0.01, 0.1, 1, 5 or a range including and / or spanning the aforementioned values. The pre-defined flow rate allows the user to remove heat at a pre-determined rate. In some embodiments, the flow of coolant can be automatically stopped when the laser is off to avoid cooling the tissue. Flowing coolant through the laser catheter assembly during laser treatment (e.g., when the laser is off) cools the surrounding tissue (e.g., from near 30-37°C) to the temperature of the coolant (e.g., near 21-23°C). In some embodiments, this has the effect of creating undertreatment due to the additional temperature gradient that must be overcome to cause tissue ablation. In some embodiments, the combination of disclosed features allows for tight regulation of cooling. In some embodiments, this temperature control can advantageously delay coagulation of tissue adjacent to the laser catheter until the end of a timed treatment. In some embodiments, delayed photocoagulation can aid in treating tumor tissue at greater distances from the laser catheter, since increased light scattering resulting from coagulation effectively attenuates light penetration into the tissue, as nanoparticles are only activated by light photons.

[0096] In some embodiments, the coolant collection bag 309 collects the coolant after one pass through the laser catheter assembly 101. In some embodiments, the coolant collection bag 309 may be connected to the laser catheter assembly 101 via the coolant outlet conduit 311 and the outlet conduit connector 324 (see FIGS. 5A-5B). In some embodiments, the volume of the coolant collection bag 309 may be about 1.5 liters, 2.0 liters, or 3 liters or more. In some embodiments, this volume allows for collection throughout the treatment period. In some embodiments, the treatment duration may be equal to or at least about 62 standard 3 minute treatments at 8 mL / min using a foot switch activated pump. In some embodiments, the coolant collection bag 309 has an integral 1.5 m tubing set that allows for placement at the bedside.

[0097] In some embodiments, a trocar assembly 400 may be provided. In some embodiments, the laser delivery system may include a trocar assembly 400 along with the laser delivery device assembly 101. In some embodiments, the probe 113 of the laser catheter assembly 101 may be introduced into a tumor or organ of tumor tissue using a trocar assembly 400 consisting of a trocar 425 with a sleeve catheter 426 (e.g., catheter sheath) wrapped around the trocar 425. As shown in FIG. 2B, in some embodiments, the introducer probe 113 may be pliable and / or flexible (e.g., a 25 cm long probe may be looped without kinking). In some embodiments, the tip may be constructed of a material that allows bending that advantageously allows the tip to avoid obstacles in the tissue. In some embodiments, as disclosed elsewhere herein, the flexible material of the probe may advantageously be less likely to stick to tissue and / or may be non-adhesive and / or may be substantially non-adhesive. In some embodiments, the introducer probe 13 has a length (e.g., from proximal to distal end) of about 300 mm, 240 mm, 200 mm or less: 300 mm, 240 mm, 200 mm, or ranges inclusive and / or spanning the aforementioned values. In some embodiments, the introducer probe has a width of about 2 mm, 1 mm, 0.5 mm, or ranges inclusive and / or spanning the aforementioned values.

[0098] In some embodiments, to facilitate introduction of the introducer probe 113, a trocar sleeve assembly 400 can be used to insert the introducer probe 113 into tissue, as shown in FIGS. 6A-6A-2. In some embodiments, as shown in FIG. 6A, the trocar sleeve assembly 400 can include a trocar 425 and a sleeve catheter 426 (e.g., a probe sheath). In some embodiments, the trocar 425 can include a trocar lumen 428. FIG. 6A-1 shows a bisection view of the trocar assembly 400 with the lumen 428 exposed. FIG. 6A-4 shows an end view of the trocar sleeve assembly 400. FIGS. 6B and 6B-1 show the trocar 425 without the sleeve, and FIG. 6B-1 shows the bisection view. In some embodiments, the trocar 425 can also include a trocar handle 429, as shown. In some embodiments, the trocar handle 429 can be ergonomic. In some embodiments, the trocar handle 429 has one or more finger loops 431 that facilitate manipulation of the trocar 425 during placement. In some embodiments, the trocar handle 429 enables placement of the trocar through the patient's tissue and / or positioning of the trocar assembly 400 within the patient at a treatment site.

[0099] In some embodiments, the trocar 425 can include a three sided cannula and / or needle 430. Figure 6A-3 is a close-up view of the catheter tip 430 with a sheath 426. Figure 6B-2 is a close-up view of the catheter tip 430 without the sheath 426. Figure 6B-3 is a front view of the trocar tip 430. In some embodiments, the three sided cannula and / or needle 430 can include a three sided cannula and / or needle 430. Figure 6A-4 is a close-up view of the catheter tip 430 with a sheath 426. Figure 6B-5 is a front view of the trocar tip 430. The trocar tip 430 avoids pulling on tissue as the trocar is pushed through the patient's tissue. In some embodiments, a beveled needle may be pulled on the bevel side as it passes through tissue. In other embodiments, a beveled needle may be used as the trocar (not shown). Figure 6B-4 is an end view of the trocar 429.

[0100] In some embodiments, after the trocar sleeve assembly 400 is inserted into the treatment site, the trocar 425 can be removed from the patient's body. In some embodiments, the catheter sheath assembly 427 can be left in the patient's body when the trocar 425 is removed. In some embodiments, the catheter sheath 426 can then be used to position the introducer probe 113 of the laser catheter assembly 101 at the treatment site. In some embodiments, as shown in FIG. 6A-1, the probe sleeve 426 can include a connector 440. In some embodiments, the sleeve connector 440 (e.g., a connector of a catheter sheath) can include one or more connection structures as disclosed elsewhere herein. In the example shown in FIG. 6A-1, the connection structure can include a ridge 440a that can be screwed into the shroud 151 of a corresponding sheath connector 150. For example, as disclosed elsewhere herein, in some embodiments, as shown in Figure 2A, the sheath connector 150 can optionally include a shroud 151 (e.g., a hood, a threaded shroud, etc.), and the connector of the catheter sheath 440 can have a female connection with a female receiver 441. In some embodiments, the connection structure can include threads, catches, arms, latches, protrusions, recesses, tapers, or any combination of the foregoing.

[0101] One or more advantages of the disclosed devices and components become apparent when performing a method utilizing a system as disclosed herein. One embodiment of the method is illustrated in Figures 7A-7K. In some embodiments, the method can include inserting a trocar assembly 400, including a trocar 426 and a catheter sheath assembly 427 sheathed about the trocar 426, into a patient at an insertion point (e.g., a first insertion point). Such insertion is illustrated in the drawings of Figures 7A-7K with a test specimen 700 representing a target tissue (e.g., a tumor, etc.). In this case, the test specimen is a raw chicken breast. The test specimen is used as a model of a tumor or an organ that constitutes a tumor.

[0102] FIG. 7A shows the test specimen and trocar sleeve assembly 400 in a protective cover 433. In some embodiments, the trocar sleeve assembly can include a trocar. FIG. 7B shows the trocar sleeve assembly 400 removed from the protective cover 433. As shown in FIG. 7C, in some embodiments, the trocar sleeve assembly 400 can be inserted into the proximal side 701 (e.g., proximal portion, where proximal refers to the location of the user and / or the insertion point) of the target tissue (e.g., test specimen 700). In some embodiments, as shown in FIG. 7D, the trocar sleeve assembly 400 can be inserted through the body of the target tissue to the distal side 702 or substantially distal side of the target tissue 700. In some embodiments, the trocar sleeve assembly can be positioned at a position intermediate between the proximal and distal sides of the target tissue. In FIG. 7D, the trocar 425 can be seen on the distal side 702 of the target tissue. 7E, in some embodiments, once the trocar catheter assembly reaches distal to the target tissue 702, the trocar 425 can be removed while leaving the catheter sheath 426 in place. In some embodiments, proper positioning of the trocar sleeve assembly 400 (or trocar, trocar tip, and / or catheter sheath 426) can be achieved using MRI, ultrasound, or other real-time imaging (e.g., computed tomography).

[0103] In some embodiments, the laser catheter assembly 101 can be prepared for insertion into the catheter sheath, as shown in FIG. 7F. As shown, the introducer probe 113 of the laser catheter 101 has an illumination radius 111 that exists around the diffuser tip when the laser can be activated. In some embodiments, the optical fiber 202 can be placed inside the laser catheter assembly 101 before inserting the introducer probe 113 into the catheter sheath 426. In some embodiments, the optical fiber 202 can be secured within the laser catheter assembly 101 via engagement of the optical fiber connector 222 with the end opening 220. As shown in FIG. 7L, the optical fiber 202 can be placed within the probe 113. In some embodiments, the optical fiber and its diffuse tip 204 can transmit laser radiation through the dome-shaped end 115 of the introducer probe 113.

[0104] In some embodiments, the introducer probe 113 of the laser catheter assembly 101 can be inserted into the catheter sheath 426, as shown in FIG. 7G. This guides the active tip of the catheter to the distal side 702 of the target tissue 700. In some embodiments, the catheter sheath assembly 427 can include an insertion port 432 and a sheath 426, as shown in FIG. 7E. In some embodiments, the insertion port 432 and the sheath 426 facilitate the insertion of an instrument, such as the introducer probe 113. In some embodiments, the laser illuminator probe 113 can be inserted into the sheath 426 of the sheath assembly 427 via the insertion port 432. As shown in FIG. 7G, the position of the probe 113 within the tissue can be determined using the catheter sheath connector 440 and scale marks on the proximal portion of the probe 113. In some embodiments, the position of the catheter sheath connector indicates to the user when the probe has reached the appropriate depth within the target tissue 700. In some embodiments, in addition to or alternatively to using the scale on the probe 113, the initial positioning of the probe 113 within the target tissue can be determined by the resistance felt by the user and resulting from tissue not penetrated by the trocar.

[0105] Once the appropriate and / or desired depth is reached, the catheter sheath assembly 727 can be slid back along the probe 113, as shown in FIG. 7H. In some embodiments, after the introducer probe 113 reaches the appropriate and / or desired location in the target tissue (as shown in FIG. 7G), the sheath assembly 427 can be retracted proximally of the target tissue 700 to expose the diffuser tip 223 in the introducer probe 113 and begin irradiating the target tissue (as shown in FIG. 7H). With the sheath assembly 427 retracted, as shown in FIG. 7H, the sheath connector 150 of the laser illuminator assembly 101 can be used to engage the catheter sheath connector 440 to secure the catheter sheath assembly 427 to the laser illuminator assembly 101. In some embodiments, the connecting structure of the connector of the catheter sheath 440 and the connecting structure of, for example, the shroud 151 of the sheath connector 150 can be sandwiched together to provide a connection between the catheter sheath 426 and the probe 113 of the laser illuminator assembly.

[0106] As shown in FIG. 7G, if the catheter sheath 426 is not transparent (e.g., not optically transparent or transmissive to the radiation emitted from the tip), the radiation may be partially blocked by the diffuser tip. As shown in FIG. 7H, when the catheter sheath 426 is withdrawn (e.g., pulled proximally) from the tissue leaving the tip of the probe exposed (into the tissue), radiation may be emitted from the tip into the tissue providing the irradiation area 710. In some embodiments, the connector 440 of the catheter sheath 426 and the sheath connector 150 of the laser irradiation device assembly 101 may be engaged (e.g., connected) as shown in FIG. 7H. In some embodiments, the connector 150, When 440 can be engaged with one another, the probe is not masked by the catheter sheath. For example, in some embodiments, the catheter sheath assembly can be a fraction of the length of the probe. In some embodiments, the catheter sheath assembly can have a length equal to or less than 9 / 10, 7 / 8, 4 / 5, 3 / 4, 2 / 3, or 1 / 2 the length of the probe (e.g., from the tip of the probe to the sheath connector).

[0107] In some embodiments, the catheter sheath 426 can be used to mask the probe 113 and / or prevent irradiation of tissue from the probe. For example, in some embodiments, the laser can be turned on with cooling water running throughout the irradiation procedure. In some embodiments, the laser can be shut off during repositioning of the probe and / or after the irradiation period has ended. For example, the connector 150, 440 can be disconnected and the scale on the probe can be used to determine when the probe is masked and no longer substantially irradiating tissue. Alternatively, in other embodiments as disclosed elsewhere herein, the laser can be turned off during repositioning and / or after the irradiation period has ended.

[0108] In some embodiments, the tip of the probe can be exposed within the target tissue and the first region 710 can be illuminated while the connector of the catheter sheath 440 and the sheath connector 150 are proximal to each other and / or engaged with each other, as shown in Figure 7H. In some embodiments, the first region can be illuminated for a predetermined and / or defined period of time.

[0109] During the irradiation time, previous laser irradiator assemblies required the user to hold the laser irradiator assembly by hand. If the user let go of the laser irradiator assembly 101 during the irradiation time (so that the weight of the body 102 of the laser irradiator assembly is placed on the probe 113), there was a significant risk that the delicate and flexible probe 113 of the laser irradiator assembly 101 would bend, kink, or break. If the probe 113 is kinked or damaged, cooling water may leak (e.g., through crevices in the probe) and the cooling of the optical fiber may not be effective. Damage to the probe may lead to ineffective radiation distribution and / or ineffective treatment of the irradiated area (e.g., due to carbonization of the tissue around the probe blocking the spread of radiation). Some embodiments disclosed herein address this and other issues. In some embodiments, the probe can be configured to be coupled to a stabilization device (e.g., the catheter sheath assembly 427), so that the probe can be protected from damage during the procedure. In some embodiments, with the disclosed configurations, the laser illuminator assembly 101 does not need to be held in place (e.g., can be released) during illumination, as the stabilizing device prevents and / or reduces damage to the probe (by bending or breaking). Because illumination can be tedious and / or require long illumination times, and because the laser illuminator assembly can be quite delicate in some embodiments, the use of stabilizing features can be particularly advantageous in ensuring that delicate probes do not kink, bend, or break when properly positioned, or in reducing the risk that the probe will kink, bend, or break when properly positioned.

[0110] In some embodiments, the stabilizing device can be configured to surround a portion of the probe and connect to the laser assembly via a sheath connector. In some embodiments, the stabilizing device provides support and / or additional strength to the probe in the portion of the probe between the patient's body and the body 102 of the laser delivery system. In some embodiments, the stabilizing device can be the catheter sheath assembly 427 and / or the catheter sheath, as disclosed elsewhere herein. In some embodiments, the stabilizing device can be the catheter sheath assembly 427 and / or the catheter sheath, as disclosed elsewhere herein. In some embodiments, the laser applicator assembly can be configured to engage the catheter sheath 426 (e.g., via the connector 426 and the sheath connector 150). In some embodiments, when the sheath connector is engaged to the connector sheath via the catheter sheath connector, the probe can be stabilized. In some embodiments, when the sheath connector is engaged to the connector sheath via the catheter sheath connector, kinking or damage to the probe can be avoided, minimized, and / or reduced in frequency.

[0111] In some embodiments, using some configurations disclosed herein, the catheter sheath assembly 427 can be used as a stabilizing device (e.g., when coupled to a sheath connector) instead of being forced to hold the probe by the body 102 of the laser illuminator system 101 during a procedure. In some embodiments, the user can let go of the laser illuminator assembly 101 and / or have the assembled probe 113 and catheter sheath assembly 427 support the entire weight of the laser illuminator assembly 101.

[0112] In some embodiments, the sheath assembly adds rigidity and / or strength to the laser assembly 101 when engaged via the connectors 150, 440. In some embodiments, when the sheath connector 150 is engaged to the connector sheath 426 via the connector 450 of the catheter sheath assembly 427, the laser applicator assembly 101 can be held by the probe in a position where the probe can be horizontal without twisting the probe.

[0113] Although engaging the catheter sheath connector 440 and the sheath connector 150 together can have certain advantages, the catheter sheath connector 440 and the sheath connector 150 need not be engaged in all cases. In some embodiments, the proximity of the catheter sheath connector 440 and the sheath connector 150 can provide stabilization of the probe.

[0114] As shown in Figures 7H-7J, in some embodiments, after irradiation of the first region is completed, the introducer probe 113 can be withdrawn slightly toward the proximal side 701 of the target tissue 700 and away from the distal side 702 to expose a second region of the target tissue (second irradiation region 7712) to treatment. In some embodiments, the withdrawal / irradiation process can be repeated multiple times depending on the size of the target tissue. After the probe is withdrawn, as shown in Figure 7I, the catheter sheath assembly 427 can be withdrawn. In some embodiments, the connectors 150, 440 can be coupled to perform treatment in the second region 712, as shown in Figure 7J. Although not shown, in some embodiments, a third, fourth, fifth, and additional regions can be irradiated. In some embodiments, the hash marks 121 on the laser catheter assembly 101 allow the user to determine the appropriate location of the first, second, third, fourth, etc. region for irradiation as the introducer probe 113 is withdrawn. After treatment is completed, the probe 113 and sheath assembly 427 can be fully withdrawn, as shown in FIG. 7K.

[0115] In some embodiments, the introducer probe 113 and / or the introducer probe and catheter sheath assembly 427 can be incrementally withdrawn from the target tissue at distances equal to or less than about 4 mm, about 8 mm, about 12 mm, values ​​between the aforementioned values, or ranges spanning and / or including those values. In some embodiments, the distance between irradiated areas of the target tissue can be equal to or less than about 4 mm apart, about 8 mm apart, about 12 mm apart, values ​​between the aforementioned values, or ranges spanning and / or including those values. In some embodiments In this case, the distance between the illuminated regions can be determined using the scale on the introducer probe.

[0116] Although not shown, in some embodiments, the distance between the irradiated regions can be determined using a scale on the catheter sheath. For example, in some embodiments, the catheter sheath of the catheter sheath assembly can be scaled. In some embodiments, the introducer probe can be initially positioned in the catheter sheath in the target tissue, and then the catheter sheath can be engaged to the probe via the connector 150, 440. In some embodiments, the introducer probe 113 and / or the introducer probe and catheter sheath assembly 427 can be incrementally withdrawn together from the target tissue at a distance equal to or less than about 4 mm apart, about 8 mm apart, about 12 mm apart, values ​​between the aforementioned values, or ranges spanning and / or including those values. In some embodiments, the distance between the irradiated regions of the target tissue can be equal to or less than about 4 mm apart, about 8 mm apart, about 12 mm apart, values ​​between the aforementioned values, or ranges spanning and / or including those values.

[0117] In other embodiments, the catheter sheath can be optically and / or transparent to radiation emitted by the ablation. In some embodiments, graduations on the introducer probe can be visible through the catheter sheath 426 to facilitate visualization of insertion depth into the patient during the procedure.

[0118] In some embodiments, the trocar sleeve assembly 400 may be reinserted into another area of ​​the target tissue (e.g., a laterally located second insertion point) and the irradiation and withdrawal process described above may be repeated. In some embodiments, after irradiation, the laser assembly may be repositioned to a different area of ​​the tumor.

[0119] In some embodiments, as with the test samples shown in FIGS. 7A-7K, a method of treating a tumor or tumor in a target region (e.g., a tumor in an organ or gland) may include a step for positioning a trocar sleeve assembly 400 in a patient. In some embodiments, the trocar sleeve assembly may be positioned by passing the trocar assembly through, for example, a prostate tumor, such that the trocar assembly passes through the proximal aspect of the tumor (toward the user inserting the trocar sleeve assembly) and terminates at the distal side of the tumor (away from the user inserting the trocar sleeve assembly). In some embodiments, insertion of the trocar sleeve assembly from the proximal side to the distal side of the tumor forms a first pathway within the tumor. In some embodiments, as described with the test samples of FIGS. 7A-7K, a method of treating a tumor may include a step of withdrawing the trocar from the patient and leaving the catheter sheath assembly 427 (e.g., catheter sheath 426) within the patient in the first pathway. In some embodiments, a laser catheter assembly 101 (e.g., laser illuminator assembly) may be obtained. In some embodiments, as discussed elsewhere herein, the laser catheter assembly 101 may include one or more of an introducer probe 113 and an optical fiber 202. In some embodiments, as shown in Figures 7J and 7L, the introducer probe 113 (e.g., a laser introducer probe) may include a first lumen and terminate in a sealed domed end configured to allow transmission of laser light. In some embodiments, as shown in Figure 7L, the introducer probe may include an inner tube located within the first lumen 116 of the introducer probe 113. In some embodiments, the inner tube 117 may include a second lumen 118. In some embodiments, as shown in Figure 7L, the optical fiber 202 may be disposed within the second lumen 118. In some embodiments, once disposed within the second lumen, the optical fiber and its diffuser tip 204 may be disposed within the introducer probe 113. Laser radiation can be transmitted through the domed end 115 of the laser probe 113. In some embodiments, the first lumen can be in fluid communication with the second lumen, when an optical fiber can be disposed within the first lumen.

[0120] In some embodiments, the method includes inserting a laser illuminator assembly into a catheter sheath 426 and guiding a laser illuminator (e.g., laser catheter assembly 101) to a first location within a first path within the tumor. In some embodiments, the first location may be proximal or distal to the tumor. In some embodiments, the catheter sheath may be partially removed to expose an introducer probe. In some embodiments, the catheter sheath may be engaged to the introducer probe using a connector 150, 440. In some embodiments, the method includes activating the laser illuminator at the first location within the first path to generate non-ablative infrared radiation for a first time, thereby heating the nanoparticles to an ablation temperature.

[0121] In some embodiments, the method includes withdrawing the laser illuminator and catheter sheath to a second location in the first pathway (and connecting via connector 150, 440). In some embodiments, the second location in the first pathway may be closer to the tumor proximally than the first location in the first pathway. In some embodiments, the laser illuminator may be activated at the second location in the first pathway to generate non-ablative infrared radiation for a second period of time. In some embodiments, the irradiation of the laser illuminator heats the nanoparticles to an ablation temperature.

[0122] In some embodiments, the method can include withdrawing the catheter and laser illuminator from the first pathway and inserting the trocar assembly into the patient at a second insertion point. In some embodiments, the second insertion point can be located laterally proximal to the tumor from the first insertion point. In some embodiments, the trocar assembly can be placed into the patient by passing the trocar assembly through the prostate tumor such that the trocar assembly passes through the proximal aspect of the tumor and terminates distal to the tumor, thereby forming a second pathway through the tumor. In some embodiments, the trocar can be removed from the trocar assembly. In some embodiments, an introducer probe of the laser illuminator assembly can then be placed into the catheter sheath. In some embodiments, the introducer probe can be guided to a first location within the second pathway within the tumor. The catheter can be moved to expose the introducer probe. In some embodiments, the first location can be located near the distal side of the tumor. In some embodiments, the first location within any pathway can alternatively be intermediate between the proximal and distal aspects of the target tissue (e.g., tumor).

[0123] In some embodiments, the laser illuminator can be activated at a first location in the second path to generate non-ablative infrared radiation for a third period of time. In some embodiments, activation of the laser illuminator at the first location of the second path heats the nanoparticles to an ablation temperature. In some embodiments, similar to the procedure used in the first path, the laser illuminator (and catheter sheath) can be proximally withdrawn to a second location in the second path. In some embodiments, the laser illuminator can be activated at a second location in the second path to generate non-ablative infrared radiation for a fourth period of time, thereby heating the nanoparticles to an ablation temperature.

[0124] In some embodiments, the laser illuminators may be positioned at 1, 2, 3, 4, 5, 6, or more locations for illumination within each path. In some embodiments, the distance between irradiated areas of target tissue within a path may be about 4 mm apart, about 8 mm apart, about 12 mm apart, values ​​between the aforementioned values, or ranges spanning and / or including those values. In some embodiments, the period during which the laser is active at each location of the path (e.g., the duration of illumination) may be equal to or at least equal to about 1 minute, about 3 minutes, about 5 minutes, about 10 minutes, values ​​between the aforementioned values, or ranges spanning and / or including those values. In some embodiments, the time required to illuminate each location of the entire path may be equal to or at least about: 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, or ranges spanning and / or including those values.

[0125] In some embodiments, the irradiation and / or treatment and withdrawal method helps to prevent seeding of agents (e.g., cancer cells, etc.) along the treatment path. In some embodiments, the withdrawal method also helps to cauterize the tissue to prevent bleeding as the instrument is withdrawn. In some embodiments, withdrawing the laser catheter assembly from distal to proximal of the target tissue can clot blood and / or substantially or completely seal off any bleeding. In some embodiments, withdrawing the laser catheter assembly from distal to proximal of the target tissue can allow blood flow to diffuse tumor cells, or push cancer cells out of the target tissue, etc.

[0126] In some embodiments, the insertion and withdrawal methods and / or other methods disclosed elsewhere herein can be performed on tumor tissue, glands that make up cancerous tissue, organs that make up cancerous tissue, and / or structures that make up cancerous tissue (e.g., the pharynx). For example, when treating the prostate, an introducer probe can be inserted distally through the prostate and withdrawn as described elsewhere herein.

[0127] In some embodiments, for tumors or treatment areas with a lateral width of more than 8 mm, multiple insertions of the laser catheter assembly laser introducer probe (or probes) can be used, since infrared light can penetrate approximately 4 mm laterally from the introducer probe. When using multiple insertion points, freehand placement of the laser introducer (or placement using a ruler, for example, to maintain the spacing of the laser shots) can result in improper placement of the laser catheter assembly. The possibility of improper placement can be high in intracavity treatments, since it may be possible to set the separation of the laser catheter assemblies only at the skin surface. In some embodiments, for tumors or treatment areas with a lateral dimension of more than 8 mm, a device for simultaneously positioning multiple laser catheter assemblies (or repeating the individual placement of a single laser catheter assembly) can be used to maintain a constant separation between the penetration points. In some embodiments, this device can be a type of template (e.g., a grid or jig).

[0128] In some embodiments, a grid or template can be used to determine the insertion point of the trocar sleeve assembly into the target tissue (e.g., tumor), as described elsewhere herein. In some embodiments, a template grid having laterally spaced holes can be used to guide the placement of the trocar sleeve assembly. In some embodiments, each insertion point in the patient's tissue can be determined by the spacing of the holes in the template grid. In some embodiments, the lateral distance between insertion points determined by the template grid can be equal to or less than about 4 mm apart, about 8, mm apart, about 12 mm apart, values ​​between the aforementioned values, or ranges spanning and / or including those values. In some embodiments, the lateral distance between insertion points can be equal to or less than about 4 mm apart, about 8 mm apart, about 12 mm apart, values ​​between the aforementioned values, or ranges spanning and / or including those values. In some embodiments, multiple insertions (e.g., multiple probes from multiple laser catheters) can be used to guide the placement of the trocar sleeve assembly. In some embodiments, the lateral distance between insertion points can be equal to or less than about 4 mm apart, about 8 mm apart, about 12 mm apart, values ​​between the aforementioned values, or ranges spanning and / or including those values. (insertion of) can be performed simultaneously using a grid. In some embodiments, the insertions can be performed sequentially using a single laser catheter and grid.

[0129] In some embodiments, a grid template, such as that shown in FIG. 8A, can be used to set and / or position the laser catheter assembly at a selected interval and / or to maintain parallel alignment of multiple penetrations of the laser catheter assembly introducer probe. In some embodiments, the use of a grid helps to prevent or reduce the amount of untreated margins of the tumor that may result if the laser dose is insufficient for particle activation, for example, due to improper probe placement. In some embodiments, the grid can include multiple openings 801. In some embodiments, each grid opening 801 can be configured to receive a sheathed trocar 425, a catheter sheath 426, and / or an introducer probe 113. In some embodiments, once the trocar 425 is positioned at the target tissue, it can be removed leaving behind the catheter sheath 426. The introducer probe 113 of the laser catheter assembly 101 can then be inserted into the sheath 426 to perform irradiation methods as disclosed elsewhere herein. In some embodiments, multiple (2, 3, 4, 5, 6, 7, 8, 9, 10, or more) laser catheter assemblies 101 and introducer probes 113 can be inserted into multiple sheaths 426 positioned using a grid, as described elsewhere herein. The introducer probes 113 can then be withdrawn together or sequentially during treatment (thereby reducing the time required to treat the target area). In some embodiments, a guidewire can be used. In some embodiments, a guidewire may not be used to position the laser catheter assemblies.

[0130] In some embodiments, a hexagonal grid 802 can be used as shown in FIG. 8A. In some embodiments, the hexagonal grid 802 can be used to provide equidistant spacing for the nearest probes. A square configuration grid 850 is shown in FIG. 8B. As shown, the grid openings 851 of the square configuration grid 850 align to provide a square shape 852. As described in FIG. 8A and FIG. 8B, labeled markers 803, 804, 853, 854 can be used to indicate where the laser catheter should be placed within the grid 800, 850. As shown in FIG. 8A and FIG. 8B, the labeled markers can include alphabetic indicators 803, 853 (e.g., A, B, C, D, E, F, G, H, I, J, K, L, M, N, O, P, Q, R, S, T, U, V, W, X, Y, Z, AA, etc.) or numeric indicators 804, 854 (e.g., 1, 2, 3, 4, 5, etc.) on different axes of the grid. Other indicators may also be used, such as color (e.g., red, orange, yellow, green, cyan, blue, indigo, purple, magenta, pink, brown, white, gray, black), shape (square, circle, triangle, diamond, pentagon, hexagon), or a mixture of color-coded shapes.

[0131] While a square grid as shown in FIG. 8B allows for easy identification of grid locations, it suffers from certain drawbacks as shown in FIGS. 8C and 8D. FIG. 8C shows a hexagonal embodiment with a minimum aperture spacing of 7 mm. FIG. 8D shows a square configuration with an aperture spacing of 3 mm. First, for a square grid with 3 mm spacing (as shown in FIG. 8D), for example, the grid locations can be 3 mm apart on both axes. This means that a translation along the diagonal corresponds to a translation of 4.24 mm, as shown in FIG. 8D. Thus, to fully cover the lateral extent of a tumor with a light transmission radius of 4 mm, the square grid requires "oversampling." That is, for a 3 mm by 3 mm grid, alternating grid locations should be used along the major axes, but along the diagonals there will be potential untreated areas unless each diagonal grid location is used. This dictates which grid locations should be used to fully cover the target area. This leads to time-consuming treatment planning to calculate which locations should not be filled and which locations can be bypassed. As shown in Figure 8D, a square pattern of nine grid locations with 3 mm spacing shows the non-overlapping areas (white) when lateral locations are not filled.

[0132] In some embodiments, by employing a hexagonal grid arrangement, some of which are shown in FIG. 8C, these difficulties are avoided since each nearest neighbor location can be equidistant. In some embodiments, once the boundaries of the treatment zone are defined, all interior grid locations can be used, providing full coverage of the target zone with minimal overlap. This provides the dual benefit of reducing (and / or minimizing) the number of introducer penetrations into the patient, and reducing (and / or minimizing) the number of treatment times. In some embodiments, a spacing of 7 mm between grid openings can be used to ensure a maximum distance of 4 mm from any grid location. FIG. 8C shows three grid locations spaced 7 mm apart, showing the convergence of treatment zones with a radius of 4 mm. As seen in FIG. 8C, in some embodiments, the maximum distance at the center of each triad of holes can be set to 4 mm. As a result, using adjacent holes for laser placement ensures continuous coverage of the area with minimal redundancy, allowing for the most efficient use of treatment time. In some embodiments, the spacing between adjacent grid openings can be less than or equal to about 5 mm: 5 mm, 4 mm, 3 mm, 2 mm, values ​​between the foregoing values, or ranges spanning those values.

[0133] In some embodiments, the grid can be prepared using a monolithic structure (e.g., one-piece design). In some embodiments, the grid can be machined by computer numerical control milling from a single piece of plastic. In some embodiments, lettering and numbering (e.g., indicators) can be etched into the plastic and / or printed on the surface. In some embodiments, the monolithic design can differ from the three-piece template grid shown in FIG. 8E. In some embodiments, the opening size can be up to about 20 gauge, 14 gauge, 12 gauge, values ​​between the aforementioned values, or a range spanning those values.

[0134] In some embodiments, each number and letter designation in the square grid covers two holes, both vertically and horizontally, resulting in twice the ambiguity in both axes for a given callout. In some embodiments, the 7 mm spacing of the hexagonal grid (as shown in FIG. 8A) allows for unambiguous identification of all positions, as well as horizontal lines printed or engraved on alternating rows of holes to facilitate accurate identification. Drawings of hexagonal and square grid embodiments are shown in FIGS. 8F and 8G, respectively.

[0135] In some embodiments, during treatment, the laser illuminator may be actuated by an actuator that may be controlled by a user. In some embodiments, when a user activates the laser illuminator using the actuator, coolant automatically flows into the first inlet of the laser illuminator assembly. In some embodiments, when the laser illuminator is inactive and may not irradiate tissue, coolant does not flow into the laser illuminator assembly. In some embodiments, the actuator may be a foot pedal.

[0136] In some embodiments, the laser power can be absorbed by the nanoparticles in the tissue, as discussed elsewhere herein. In some embodiments, upon absorption, the nanoparticles heat up to a sufficiently high temperature to induce photothermal coagulation of the tissue. In some embodiments, photothermal therapy with nanoparticles can be performed using a laser of sufficiently low power (e.g., 3.5-4.5 W / cm diffuser) so as not to induce coagulative hyperthermia by itself. In some embodiments, the power of the laser can be about 2 W / cm, 3 W / cm, 4 W / cm, 5 W / cm, 6 W / cm, or a range spanning and / or including these values. In some embodiments, coagulative thermotherapy occurs when the nanoparticles absorb the radiant energy. In some embodiments, non-coagulative thermotherapy can be induced at temperatures of about 45° C. or less, about 35° C. or less, about 30° C. or less, or a range spanning and / or including these values. In some embodiments, coagulative temperatures include tissue temperatures equal to or greater than about 45° C. In some embodiments, the laser can be operated for a period of about 3 minutes to about 5 minutes without inducing temperatures that cause photothermal coagulation.

[0137] In some embodiments, the laser illuminator emits radiation having a near-infrared wavelength. In some embodiments, the nanoparticles can be designed to have an optical absorption maximum in radiation in the near-infrared region (e.g., wavelengths ranging from about 670 nm to about 1200 nm) that allows the penetration of this energy into normal tissue. In some embodiments, upon application of a laser emitting within these wavelengths, the nanoparticles absorb this energy and convert it into heat, raising the temperature of the tumor to ablation levels. In some embodiments, the effect of nanoparticle-induced hyperthermia is to produce a temperature increase limited to the tumor and the area immediately adjacent thereto, localizing the tissue ablation area and reducing damage to the surrounding healthy tissue. In some embodiments, the laser illuminator emits radiation having a near-infrared wavelength in the range of about 805 nm to about 810 nm. In some embodiments, wavelengths of about 805 nm to about 810 nm allow for increased absorption of the nanoparticles while allowing for low absorption by tissue (and hemoglobin). In some embodiments, wavelengths of about 1000 nm can be used.

[0138] In some embodiments, the laser illuminator can emit radiation of insufficient power to induce photothermal coagulation of tissue. In some embodiments, the optical fiber can include a diffuser tip that distributes non-ablative infrared radiation within the tumor. In some embodiments, the laser illuminator emits radiation of between about 3.5 W / cm and about 4.5 W / cm of the diffuser tip.

[0139] In other embodiments, the lateral distance between insertion points may not be determined using a template grid.

[0140] Some embodiments relate to kits for use in laser treatment as described elsewhere herein. Figures 9A-9G show kit embodiments that may include one or more components of a laser delivery system. In some embodiments, a container having packaging may be provided as shown in Figure 9A. In some embodiments, the kit may include a light diffuser pack as shown in Figure 9B. In some embodiments, the light diffuser pack may include an optical fiber 202 having an optical fiber tip and an optical fiber connector as described elsewhere herein. In some embodiments, the light diffuser pack may include an optical fiber sheath that protects the fiber and / or the diffuser tip. In some embodiments, the kit may include a coolant supply set as shown in Figure 9C. In some embodiments, the coolant supply set may include one or more of a coolant reservoir, a coolant inlet conduit, an inlet conduit connector, a coolant collection bag, a coolant outlet conduit, and / or a coolant outlet connector. In some embodiments, the kit may include a laser catheter assembly packet. In some embodiments, the laser catheter assembly kit may include one or more of a laser catheter set assemblies 101. In some embodiments, the introducer probe 113 of the laser catheter assembly may be protected with a protective sheath 122, as shown in Figure 9D. In some embodiments, the introducer probe 113 of the laser catheter assembly may be protected with a protective sheath 122, as shown in Figure 9E. 910 (e.g., for assembly or use of the laser catheter assembly). In some embodiments, the instructions may include a drawing, such as that shown in FIG. 1. In some embodiments, a method for using the laser catheter system, such as that disclosed elsewhere herein, may be provided as part of the instructions. In some embodiments, an additional layer of packaging material may be used to cover the kit, as shown in FIG. 9F. In some embodiments, the packaging container may be closed and sealed to provide a kit ready for shipment, as shown in FIG. 9G. Although not shown, in some embodiments, the kit may further include a coolant pump, a trocar and associated devices, a grid assembly, etc. Additionally, one or more of the components shown in FIGS. 9A-9G may be omitted from the kit.

[0141] Some embodiments have been described in connection with the accompanying drawings. Although some figures are drawn to scale, such scale is not limiting, as dimensions and proportions other than those shown are contemplated and are within the scope of the disclosed invention. Distances, angles, etc. are merely illustrative and do not necessarily bear an exact relationship to the actual dimensions and layout of the illustrated devices. Components may be added, removed, and / or rearranged. Furthermore, any particular features, aspects, methods, properties, qualities, attributes, elements, etc. disclosed herein in connection with various embodiments may be used in all other embodiments defined herein. Furthermore, it will be recognized that any method described herein may be implemented using any device suitable for performing the steps referred to.

[0142] Usage example Example 1: Laser catheter inspection It has been observed that the tips of certain laser introducer probes of cooled catheter laser systems melt during clinical procedures, resulting in the formation of char on the tip and loss of light penetration into the tissue. This char also results in non-specific coagulation and heat fixation. Heating of an embodiment having a dome-shaped laser catheter tip was performed using the Visualase® cooled catheter system. A side-by-side comparison was made with a Visualase Laser Diffusion Fiber (CCCS) (with a ground conical tip). The results showed that the conical tip of the CCS created a significant heat focus, significantly exceeding that of the domed laser catheter tip. The experiments described in this example showed that the heating of the CCS was concentrated in the conical tip, with one-third to more than one-half of this heating being the result of end losses from the laser diffusing fiber (LDF). This conclusion was reached by using both the Visualase Laser Diffusing Fiber and an embodiment with a domed laser catheter tip under the same conditions in the same conical Visualase cooled catheter system. When the embodiment with a domed laser catheter tip was used, 34-57% less heat was generated than when the Visualase LDF was used in the same Visualase conical tip catheter. Without being bound to a particular theory, it is believed that excess light escaping the tip of the Visualase LDF and the conical catheter tip itself contribute to the development of hot spots that destroy the device. The remainder of the tip heating is due to the shape and material of the catheter itself. In contrast to the temperature rise of 22-57°C caused by CCS, the temperature rise at the tip of the dome-shaped laser catheter under similar experimental conditions was less than 2°C.

[0143] Test Organization The laser catheter assembly, consisting of the Visualase CCS and domed laser catheter tip, was constructed identically to one another, with an isotropic diffuser tip optical fiber secured within a clear, dual-lumen, liquid-cooled 16G catheter. Testing was performed in the field, representing a "worst case scenario" where there was no thermal coupling or heat transfer to tissue, which would tend to aid in heat dissipation from the tip. The CCS was assembled as part of a standard Visualase Cooled Laser Applicator System (VCLAS). The tip of the 11 meter LDF was advanced to within 2 mm of the end of the CCS tip. Cooling The inlet and outlet of the liquid were VCLAS tubing sets (without extension sets) supplied from a 1 L flask containing room temperature water. Cooling liquid was supplied by a Visualase K-Pump.

[0144] The experimental layout for the performed experiment is shown in Figures 10A and 10B. The coolant pump 307 and laser 203 were placed on a cart (left in Figure 10A) and connected to the CCS / LDF assembly 901 via a set of coolant tubing. The thermal camera 900 (the small object attached to an adjustable arm in the center of both Figures 10A and 10B) was operated from a laptop computer. The power supply 902 is also shown. The CCS / LDF assembly can be hung on a ring stand, shown in Figure 10B. The laser power meter is on the right side of Figure 10A.

[0145] test 1. Heating of the CCS / LDF assembly. Measured at 4.5, 6.0, and 12.0 W laser power, in air, and at nominal coolant flow rate.

[0146] 2. Heating of the CCS assembly with an 18 mm AuroLase® fiber optic diffuser instead of the Visualase LDF.

[0147] Test Conditions Air: A non-physiological condition that allows thermographic measurements and represents the "worst case scenario" for thermal conductivity.

[0148] Orientation: In all cases the CCS assembly 901 was mounted vertically, tip down.

[0149] Laser power: 4.5±0.1W with 10mm diffuser, 6.0±0.1W with 18mm diffuser, 12.0±0.1W which is twice the standard laser power.

[0150] Nominal coolant flow rate: 7.9±0.2mL / min Water, room temperature (20~21℃)

[0151] CCS experimental setup Laser Diomed 15+ #10000126

[0152] Coolant Pump: Visualase K Pump, item number 10000125

[0153] Coolant Supply: Standard AuroLase® Therapy CSS

[0154] Optical power optometer: Gigahertz-Optik P9710-2, NBI Property #10000242 / 243

[0155] Thermography 900: ICI Model 3720

[0156] Data recording and image control software: Lenovo Ultrabook Yoga 2 Pro running custom ICA IRFlash application

[0157] Test Article The cooling catheter assembly with the laser diffusing fiber was advanced to 2 mm from the catheter tip.

[0158] Cooled catheter assembly with an 18 mm fiber optic diffuser advanced 2 mm from the catheter tip.

[0159] Figures 11A and 11B show data for the Visualase® Cooled Catheter System (CCS) (with a ground cone tip; Figure 11A) and a dome-shaped laser catheter tip as disclosed elsewhere herein (Figure 11B). Figure 11A shows the peak temperature rise at the distal end of the CCS assembly over a 3 minute period with laser powers of 4.5 W, 6.0 W, and 12.0 W. Coolant flow was uninterrupted and set at 7.9 mL / min from a 1 liter reservoir at room temperature (20°C). Temperatures followed a characteristic first-order transient response. At 4.5 W the temperature rise was 22°C, at 6.0 W the temperature rise was 28°C, and at 12.0 W the temperature rise was 57°C. Settling in final temperature was fast, with time constants ranging from 1.9 to 2.9 seconds, reaching an average within 15 seconds in all cases.

[0160] Figure 11B shows the heating of a laser catheter assembly consisting of a dome-shaped laser catheter tip under the same heating conditions as when the Visualase system was irradiated in Figure 11A. In comparison, the laser catheter assembly consisting of a dome-shaped laser catheter tip with 12.0 W irradiation increased the temperature by 1.2 to 1.6 °C above ambient temperature during a standard 3-minute treatment. Figure 11B shows the heating of a laser catheter assembly consisting of a dome-shaped laser catheter tip under nominal (6.0 W / 18 mm diffuser) and double laser power for both Assembly #1 (circle) and Assembly #2 (square). Assemblies #1 and #2 are two identical optical fiber / laser catheter assemblies tested under identical conditions. The assemblies were cooled with room temperature water at 8.0 mL / min. Figures 11A and 11B are scaled to clearly show the details of the temperature change. For example, Figure 11B shows a zoomed-in view of the temperature.

[0161] 12A and 12B show false color thermal images of the distal tip 950 of the CCS / LDF assembly and at the end of 6.0 W exposure. FIG. 12C and 12D show false color thermal images of the distal tip of one embodiment of a dome-shaped catheter at the end of 6.0 W exposure. Heat is concentrated at the very tip of the CCS, at 52.4° C., or 28° C. above ambient temperature. FIG. 12B is a close-up of the CCS / LDF tip at 6.0 W exposure, clearly showing the heat buildup at the extreme of the cone-shaped tip. From FIG. 12A, it is immediately evident that heating is concentrated within the cone-shaped tip. This is further demonstrated by the close-up of the CCS tip in FIG. 12B, showing that the hottest area is at the extreme tip of the CCS. From FIG. 12C and FIG. 12D, it is evident that there is no heat buildup at the tip of the dome-shaped cooled catheter.

[0162] 2. Heating the CCS / OFD Assembly The heat generation from the different laser catheters has two sources: the fiber optic diffuser itself and the material and geometry of the catheter envelope. To distinguish between these two contributions, the fiber optic diffuser of the laser catheter system described elsewhere herein was substituted for the CCS and the laser irradiation was repeated.

[0163] FIG. 13 shows the temperature rise of a CCS using one embodiment of a laser diffuser disclosed herein (with an 18 mm diffuser tip) in place of the Visualase Laser Diffusing Fiber. FIG. 13 records the peak temperature rise at the distal end of the CCS / OFD assembly over a 3 minute period with laser powers of 4.5, 6.0, and 12.0 W. The flow rate of the coolant was set at 7.9 mL / min delivered from a room temperature (20° C.) 1 liter reservoir and was uninterrupted. The temperature also followed a characteristic first order transient response. At 4.5 W it rose by 9.4° C., at 6.0 W it rose by 12.3° C., and at 12.0 W it rose by 38° C. Settling at the final temperature was less rapid than in the past, with time constants ranging from 2.2 to 4.8 seconds, and equilibrium was essentially reached within 25 seconds. Overall, the change from LDF to OFD resulted in a significant improvement in the temperature rise at 4.5 The heat generation was reduced by 57% at 1.0 W output, 56% at 6.0 W output, and 34% at 12.0 W output. Because heating of the CCS occurs predominantly at the conical tip, it was concluded that: 1) the 34-57% reduction in heating obtained by switching to the optical diffuser disclosed herein can be the result of significantly reduced end losses from the diffuser tip.

[0164] conclusion A tendency for the conical tips of cooled catheter systems to melt during clinical procedures has been observed, resulting in the formation of char on the tip, loss of light penetration into the tissue, and nonspecific coagulation and heat fixation. One-third to more than one-half of this heating is due to end losses from the laser diffusing fiber, with the remainder due to the shape and material of the catheter itself. In contrast, the temperature rise of 22-57°C for CCS resulted in less than 2°C of temperature rise using an embodiment of the laser catheter assembly as disclosed herein (e.g., an embodiment as disclosed herein having a domed tip) under approximately the same conditions.

[0165] Example 2: Treatment of prostate tumors This is a single-arm study with one patient group. The aim of this study is to determine the efficacy of localized ablation of prostate tissue with nanoparticle-directed laser irradiation using MRI / US fusion imaging technology.

[0166] The patient population consisted of men with low- to intermediate-risk localized prostate cancer visualized on MRI and with localized areas of prostate cancer confirmed using MRI / US Fusion Guided Biospy. Patients also had no lesions detected by ultrasound-guided biopsy outside the areas visualized on MRI.

[0167] The study has one arm / group: up to 45 patients will receive a single intravenous injection of AuroShell® particles 12-36 hours prior to MRI / US-guided laser irradiation using an FDA-approved laser and interstitial fiber optics.

[0168] Contrast-enhanced MRI can be performed 48-96 hours after laser irradiation to assess the effectiveness of resection and acute volume prior to the appearance of coagulative necrosis and tissue remodeling due to lytic effects. On MRI, the appearance of a "cavitation" rather than reduction in lesion size is generally expected.

[0169] The efficacy of localized ablation of prostate tissue will be assessed by MRI / ultrasound-guided biopsy at 90 days (primary endpoint) and one year after laser treatment. Standard of care involves six-month follow-up after one year, which was outside the scope of the initial study.

[0170] Nanoparticle Dose: This study used AuroShell®, which is a gold nanoshell. AuroShell® Dose: Each patient received 100 optical densities (approximately 2.77×10 11 AuroShell® particles will be infused at a maximum volume of 7.5 mL / kg, concentrated to 100 particles / ml or 36 mg particles / kg patient body weight. AuroShell® particles will be administered intravenously through a standard non-DEHP infusion set and infused at rates ranging from 120 mL / hour to a nominal 600 mL / hour at the investigator's discretion.

[0171] Laser irradiation: Laser irradiation is performed under ultrasound guidance 12-36 hours after particle injection. An isotropic diffuser tip fiber in a water-cooled jacket can be inserted transperineally. The urethra can be cooled by circulating saline (or water) through the urethral catheter. Up to 5.0 watts per cm length of the optical fiber diffuser, measuring 810±10 nm laser power, can be delivered for up to 4 minutes to each treatment site. If necessary, the laser fiber can be repositioned to irradiate different zones.

[0172] Inclusion criteria Patients have histologically or cytologically proven evidence of prostate tumor. Patients are 45 years of age or older. Patients or their legal representatives are able to read, understand, and sign informed consent. Organ-confined clinical T1C or clinical T2a prostate cancer, visualized on MR imaging. Prostate cancer is diagnosed by MR image-guided biopsy. Gleason score ≤7; and no more than two positive lesions on a previous MR US fusion-guided prostate biopsy. If a standard biopsy core is positive, the MR lesion must have been biopsied and taken from the same location in the prostate that was proven to be cancerous (left / right, base, mid-gland, apex). Previous MRI within 120 days prior to resection. No metastatic disease per NCCN guidelines (www.nccn.org). For patients with clinical T1 and PSA>20, or T2 and PSA>10 PSA>15ng / ml, a bone scan is indicated to determine the presence or absence of metastatic disease if PSA<15ng / ml, or PSA density<0.15ng / ml2. Patients provided written informed consent after being informed of the study and alternative treatment options.

[0173] Patients with known hypersensitivity to any of the components of the PEGylated gold nanoshell suspension (polyethylene glycol, gold).Patients receiving concurrent investigational drug treatment or within 5 half-lives of that investigational drug treatment prior to the date of administration of the PEGylated nanoshell particles.

[0174] Introduction Prostate cancer is the most commonly diagnosed cancer in men. In 2014, approximately 233,000 men were diagnosed with prostate cancer in the United States, and an estimated 29,000 died from the disease. The average annual incidence rate of prostate cancer in African American men was 60% higher than in non-Hispanic white men, and the average annual death rate was more than twice that of non-Hispanic white men.

[0175] Existing treatments for primary prostate cancer include "active surveillance," surgical resection, and radiation therapy (including brachytherapy). These treatments are associated with significant levels of side effects, including erectile dysfunction, urinary incontinence, and rectal problems. There is a need for localized therapeutic approaches that may reduce treatment-associated side effects and eradicate current disease or extend the time to progression.

[0176] The optical properties of tissue inherently limit the propagation depth of light energy, thereby enabling truly focal therapy. Heat generated from the energy source is inherently diffuse and non-specific. Thermal ablation heat can be propagated over millimeters, but is not specific to tumor morphology. Nanoshell particles enable more precisely localized conformal therapy, delivering tumor-specific damage on the millimeter scale.

[0177] An MRI fusion imaging approach using ultrasound guidance based on a priori MRI fusion imaging should allow precise placement of a fiberoptic catheter within or adjacent to the prostate lesion targeted for resection.

[0178] The fusion of MRI fusion imaging followed by directed placement of a laser catheter represents a means to establish the efficacy and usefulness of nanoshell therapy for focal therapeutic treatment of prostate tissue. The MRI and ultrasound fusion approach addresses limitations identified using ultrasound-only approaches.

[0179] 1) pre-treatment target planning, and 2) catheter placement planning using the Brachytherapy Stepper to allow precise placement of the laser catheter in close proximity to the lesion to be ablated. Guided imaging used as an additional level of safety after the initial use of ultrasound for

[0180] This method can also be used in head and neck squamous cell carcinoma, canine melanoma, oral cancer, and canine and human prostate, helping to demonstrate the inherent focality of particle-directed photothermal energy. Incorporation of imaging modalities allows for precise focal treatment. Furthermore, the co-localization of particles with tumor tissue allows for focal ablation tailored to the targeted tumor.

[0181] The potential advantage of nanoshell therapy is that it destroys tumors highly selectively and rapidly while minimizing damage to surrounding tissue, potentially allowing tumors to be cured with minimal toxicity. Preclinical studies have demonstrated that nanoshell therapy is effective and does not cause detectable systemic toxicity.

[0182] Clinical Trial Equipment and Systems The nanoshell and laser delivery system disclosed herein selectively destroys solid tumors using near-infrared radiation from a laser. While other energy-based ablation methods rely on endogenous absorption and conversion of deposited energy into heat, nanoshell particles are delivered systemically to the tumor and act as exogenous absorbers of this laser radiation, generating a lethal thermal response specific to tumor tissue.

[0183] Nanoshell therapy consists of three components: (i) a near-infrared laser source, (ii) an interstitial fiber optic probe for delivering the laser energy near and / or inside the tumor, and (iii) nanoshell particles, which are near-infrared absorbing inert materials designed to absorb and convert the laser energy into heat. The nanoshell particles are administered systemically and allowed to selectively accumulate at the tumor site, where they are then irradiated with a near-infrared laser. The particles absorb this radiation and convert it to heat, resulting in thermal destruction of the tumor and the blood vessels that supply it, while minimizing damage to the surrounding healthy tissue. Because particle accumulation within the perivascular space of the tumor is passive and can only rely on the palisaded neovasculature characteristic of solid tumors, nanoshell therapy can also be used in patients who have previously undergone chemotherapy and radiation therapy. During the procedure, the margins of treatment can be monitored using needle thermocouples placed around the tumor. In some embodiments, this allows for monitoring the temperature around the ablation area, minimizing the risk to the operator of overheating areas other than critical structures and the intended target tissue. A lower temperature control point (threshold of about 45° C. to about 50° C.) is used near critical structures such as the urethra, urethral sphincter, and rectal wall to avoid damage to these tissues.

[0184] Nanoshell therapy is useful for recurrent and refractory head and neck cancer and metastatic lung tumors.

[0185] The study has one arm / group. Up to 45 patients will receive a single intravenous injection of nanoshell particles 12-36 hours prior to ultrasound-guided laser treatment using an FDA-approved laser and interstitial laser fiber. A contrast-enhanced MRI will be performed 48-96 hours after laser treatment to allow time for the appearance of coagulative necrosis but before lytic tissue remodeling to assess acute efficacy and ablation volume. On MRI, the appearance of a "cavitation" is generally expected rather than lesion shrinkage.

[0186] Nanoshell / laser catheter therapy is a system for photothermal ablation of solid tumors using near-infrared energy. The system utilizes an interstitial fiber optic probe to deliver near-infrared energy emitted by an FDA-cleared laser to adjacent and / or within solid tumors. Unlike other energy-based ablation methods that rely on endogenous absorption of the delivered energy and conversion to heat, nanoshell / laser catheter therapy particles delivered systemically to the tumor act as exogenous absorbers of this laser radiation, generating a lethal thermal response specific to tumor tissue.

[0187] Nanoshell / laser catheter therapy consists of three components: (i) a near-infrared laser source, (ii) an interstitial fiber optic probe to deliver laser energy near and / or inside the tumor, and (iii) nanoshell particles, a near-infrared absorbing inert investigational material designed to absorb the laser energy and convert it to heat.

[0188] Nanoshell / laser catheter therapy can be used with any FDA-approved clinical laser that emits near-infrared energy with desired parameters (energy, duty cycle, cycle time) and an interstitial fiber optic probe for percutaneous energy delivery. The nanoshell particles used in this study consist of a gold metallic shell and a non-conductive (dielectric) core that acts as an exogenous absorber of the near-infrared laser energy delivered by the fiber.

[0189] The nanoshell / laser catheter treatment in this study uses either an FDA-approved laser, Diomed 15-PLUS (K013499) or LiteCure, LLC (K093087), as the infrared energy source, and an interstitial liquid-cooled fiber optic source.

[0190] The steps involved in nanoshell / laser catheter therapy can include one or more of: (i) intravenous injection of a dose of nanoshell particles; (ii) a time delay of 12 to 36 hours to allow accumulation of nanoshell particles within the tumor due to the enhanced penetration and retention (EPR) effect; and (iii) irradiation of the area with continuous wave (CW) or pulsed coherent light at a desired wavelength, e.g., between 800 nm and 815 nm, for up to 4 minutes with an average delivered power of up to 5.0 watts. Irradiation with an average power of 0 watts (assuming isotropic diffuse irradiation over a length of 1 cm). The nanoshell particles in the area absorb the light and the metal shell converts the absorbed light into heat, generating enough heat to thermally ablate the tumor. The applicator can be placed externally, inserted interstitially, or inserted endoscopically, and can use either a collimated or a dispersive fiber tip.

[0191] The nanoshell particles used in this study are composed of a metal shell and a non-conductive or dielectric core. These particles can be engineered to absorb or scatter light at desired wavelengths. This "tunability" can be achieved by varying the ratio of the thickness of the metal shell to the non-conductive core. The outer shell of the particle can be composed of gold, which has a long history of use in particulate form in vivo, as an implant material, or as a coating for implantable devices. The non-conductive core is silica, but can be composed of any dielectric material. For cancer therapy, nanoshell particles are engineered to absorb infrared light at wavelengths where light is poorly absorbed in human tissue. Human tissues exhibit minimal absorption in the wavelength range from 750 nm to 1100 nm, often referred to as the "water window" or "tissue optical window." While solid gold nanoparticles and microparticles absorb light at wavelengths that are also absorbed by tissue, gold-coated nanoshell particles can be engineered to absorb or scatter light within this "tissue optical window," enabling new in vivo applications.

[0192] More specifically, the nanoshell particles used in this study consist of a thin gold shell, 10–20 nm thick, deposited on a solid silica (silicon dioxide) core. To prevent particle aggregation in saline environments and to provide steric hindrance in vivo, 5000 molecular weight (MW) methoxy-polyethylene glycol (PEG) chains can be attached with thiol (sulfur) bonds. The PEG coating improves the stability of the nanoshell particles in isotonic aqueous solutions and may also improve their circulatory half-life upon administration. In the studies reported here, the particles are concentrated to the desired level (generally 0.1% by volume or less) and suspended in an isotonic aqueous solution for injection (10% trehalose in water).

[0193] Mechanism of action Lasers and radiofrequency ablation devices are used to thermally destroy tissue by delivering energy at rates that exceed the tissue's ability to dissipate energy through blood perfusion thermal diffusion. Additionally, some lasers take advantage of the natural absorbent properties of tissue and blood by delivering energy at wavelengths that are naturally absorbed by pigment bodies within the tissue and blood, converting light into thermal energy. The result is thermal coagulation of cells or thermal fixation of tissue and destruction of the vasculature.

[0194] Nanoshell particles are injected intravenously and are known to accumulate in the tumor interstitium as a result of the palisaded vasculature associated with tumors. This mode of accumulation has been established for other particles and is referred to as the EPR effect. SEM analysis of tumor tissue after intravenous injection of nanoshell particles indicates that particle accumulation may occur preferentially in the vicinity of the tumor vasculature.

[0195] The nanoshell particles are designed to absorb near-infrared energy and convert it to heat via surface plasmon resonance. The near-infrared dose levels utilized in nanoshell / laser catheter therapy can be below levels that would cause significant damage to tumor or normal tissue in the absence of the nanoshell particles. In the presence of nanoshell particles in tissue, the near-infrared dose generates a thermal response sufficient to produce photothermal coagulation, leading to cell death. This may also include the destruction or occlusion of tumor vasculature, similar to FDA-approved microspheres for embolic purposes.

[0196] Preparation of nanoshells The nanoshell particles used in this study were packaged in 80 mL aliquots in sterile IV bags and kept at 2-8°C. At the time of infusion, remove the bag from refrigeration and allow to warm to room temperature for 30 minutes. Gently knead or shake the bag to ensure even distribution of the material. Use C-Flex, non-DEHP, medical grade infusion tubing. Place a 1.2 micron filter (Pall TNA1 or equivalent) between the infusion tubing and the patient catheter.

[0197] Particle dosage and administration method Nanoshell particles are infused at a rate of 600 mL / h (10 mL / min). Vasoconstrictors are avoided for 3 days prior to and the first 6 h after administration to maximize particle accumulation in the tumor. Each patient receives a 100 optical density (approximately 2.77 × 10 11 Up to 7.5 mL / Kg of concentrated nanoshell particles (35 mg / particle / mL or 35 mg / particle / kg patient weight) will be intravenously injected.

[0198] Laser Applications Laser irradiation is performed under MRI / US fusion guidance 12-36 hours after particle injection. The urethra can be cooled by circulating saline (or water) through the urethral catheter (typ. 6-10 mL / min). An optical fiber with an isotropic diffuser tip can be intermittently inserted into a sealed catheter via a transperineal approach using a 14G needle / cannula introducer. Up to 5.0 watts of 810±10 nm laser power can be delivered to each treatment site for up to 4 minutes. If necessary, the laser fiber can be repositioned to irradiate different sites.

[0199] The specific procedure is described in the AuroLase® Therapy Instructions for Use (IFU), but is briefly outlined below.

[0200] Prior to use, calibrate the laser and ensure that the laser output through the laser fiber is up to 5.0 watts / cm average power. Prior to use, ensure that the cooling system of the laser fiber is functioning properly. Use ultrasound guidance and avoid the urethra and other critical structures. While maintaining the prostate, insert a needle / cannula introducer (e.g., trocar or catheter sheath) into the prostate proximal to the index lesion to be treated. The fusion image created by the MRI is not used to guide the laser insertion, but only as a check for insertion with ultrasound guidance. Remove the needle from the introducer and replace it with the laser catheter. Withdraw the cannula (connected to the laser catheter probe) to expose the light-emitting portion of the laser catheter. At the clinician's discretion, a needle thermocouple may be inserted in parallel with the laser catheter to monitor the temperature near the treatment area if the target lesion indicates proximity to sensitive or critical structures (e.g., urethra, prostatic capsule, nerve bundles). Irradiate the intraprostatic zone with the fiber for up to 4 minutes. If dictated by the size of the lesion to be treated, withdraw the fiber 2 mm less than the irradiation length and irradiate a new zone. Repeat as necessary to irradiate the entire lesion. Repeat steps at new sites if additional target lesions are to be treated. If a single target lesion is treated, the investigator will perform one laser treatment in the contralateral prostate hemisphere as a negative control for the laser treatment (i.e., no particle accumulation around blood vessels in tumor tissue and no thermal damage to normal tissue). If two lesions, one in each hemisphere of the prostate, are treated, this negative control procedure will not be performed. At the investigator's discretion, if a Foley catheter was used to cool the urethra during the laser treatment, this catheter may be left in place to prevent urethral obstruction as a result of thermal edema. The Foley catheter may be left in place until the follow-up MRI on days 4 / 5.

[0201] A complete physical examination (general appearance, skin, neck, ears, eyes, nose, throat, lungs, heart, abdomen, back, rectum, lymph nodes, extremities, and neurological status) can be performed at baseline and at 90-day follow-up.

[0202] A follow-up MRI fusion biopsy can be performed at 90-day follow-up to assess the effectiveness of tumor resection to determine whether there are viable cancer cells within the treated area and therefore the effectiveness of the localized resection of prostate tissue. Patients will undergo standard of care re-evaluation biopsies at 1 year and 6 months thereafter, according to their physician's treatment plan, which include an MRI / US fusion biopsy and a standard 12-core biopsy.

[0203] result Patients experience a 70-80% reduction in tumor size six months after treatment. In 25% of patients, prostate cancer is completely eradicated. In 50% of patients, no side effects are observed and normal prostate function is maintained.

[0204] Example 3 Treatment of head and neck tumors A pilot study of AuroLase® therapy in patients with refractory and / or recurrent tumors of the head and neck. This is an open-label, multicenter, single-dose pilot study of AuroLase® Therapy in the treatment of patients with refractory and / or recurrent tumors of the head and neck. Three treatment groups of five patients each will be enrolled and observed for six months after treatment. Each group will receive a single dose of AuroShell® particles. If no unexpected significant side effects are observed in group 1, this dose can be increased by up to 67% in groups 2 and 3. Laser treatment in each group will consist of one or multiple interstitial treatments (depending on tumor size), and the laser dose will be titrated in groups 2 and 3.

[0205] The first group of five patients will be treated with a minimum therapeutic level of 4.5 ml / Kg of AuroShell® particles concentrated to 100 optical density (approximately 1.3 x 10^12 particles / Kg or 29 mg particles / Kg). An isotropic fiber in a water-cooled jacket with a 1 cm diffuser tip will be intermittently inserted into and / or near the tumor, with a maximum of 3.5 watts. The fiber can deliver 800-810 nm laser power at a measured average output of 1.25 pulses / sec for up to 4 minutes at a 75% duty cycle. The fiber can be repositioned 1 cm from its initial placement to irradiate the contralateral side of the tumor or a different tumor, if appropriate precautions are taken. For tumors with an estimated thickness of >1.0 cm at the time of fiber placement, the fiber can be retracted into the catheter to illuminate the tumor mass.

[0206] After treatment of the first three patients, safety data for each patient (including data from the 4th week post-treatment visit) will be submitted as required by FDA. If there are no unexpected side effects, enrollment and treatment will continue for two additional patients (for a total of five patients in the first group of the study) who are being treated with the lowest concentration of 4.5ml / Kg. If no unexpected device adverse effects related to the AuroShell® dose are observed in group 1, the AuroShell® dose for groups 2 and 3 will be increased from 4.5ml / Kg to 7.5ml / Kg of AuroShell® particles concentrated to 100 optical density (approximately 2.1x10^12 particles / Kg or 34mg particles / Kg).

[0207] For the second treatment group of five patients, laser irradiation can be increased to a measured average power of 4.5 watts of 800-810 nm laser output delivered at 1.25 pulses per second, with a 75% duty cycle, for a duration of up to 4 minutes, provided no unexpected adverse device effects are observed in the first group.

[0208] In the third treatment group of five patients, if no unexpected adverse device effects resulting from AuroLase® Therapy are observed in group two, laser irradiation can be increased to a measured average power of 5.0 watts of 800-810 nm laser output delivered at 100% duty cycle (continuous wave) for a maximum of four minutes.

[0209] In each treatment group, AuroShell® particles are administered intravenously at a rate of 2 ml / min for the first 15 minutes, which can then be increased to a maximum of 10 ml / min. At approximately 0.5, 2, 4, 8, 24, and 48 hours after AuroShell® particle administration, 2 ml blood samples can be obtained to determine particle concentrations by dynamic light scattering analysis (DLS) and neutron activation analysis (NAA).

[0210] Approximately 12-36 hours after intravenous injection of the particles, the target tumor can be irradiated with a laser as described. After AuroLase treatment of the target lesion, a biopsy can be taken and gold accumulation can be measured by neutron activation analysis.

[0211] In addition to being observed up until the first day after laser treatment, patients will be followed up at weeks 1 and 2, and then monthly for six months after treatment.

[0212] Introduction Approximately 46,000 cases of head and neck cancer are diagnosed annually in the United States, resulting in approximately 11,000 deaths annually. Unfortunately, 5-year survival rates have not improved significantly in recent years, despite multimodality treatment including surgery, radiation therapy, and chemotherapy, all of which are associated with significant morbidity for patients.

[0213] Nanoshell therapy can be used to selectively destroy solid tumors using near-infrared light from a laser. Particles administered systemically to the tumor act as exogenous absorbers of this laser radiation, generating a thermal response.

[0214] Nanoshell Nanoshells (e.g., AuroShell®) have a diameter of about 110-125 nm. It consists of a silica core of 1000 MW (the total diameter of the particle including the gold shell can be 140-170 nm); a functionalizing molecule, APTES (3-aminopropyltriethoxysilane), for attaching the gold colloid to the silica; and a thin layer of gold (10-20 nm thick) attached to the functionalized surface of the silica core. The process of attaching the gold shell to the silica core involves the production of small colloidal gold nanoparticles with a diameter of 2-6 nm and the attachment of these nanoparticles to the amine groups present in APTES. These colloidal nanoparticles then serve as nuclei for the reduction of a gold salt (HAuC14) in the presence of formaldehyde, completing the shell layer. The gold shell can comprise approximately 95% of the particle mass. A layer of 5000 MW PEG-thiol is attached to the surface.

[0215] Dosage and Administration To enhance the EPR effect and the effectiveness of AuroLase®, increase the patient's temperature with a blanket or heating pad one hour prior to administration. A heating pad should be applied to the tumor site. Cold drinks should be avoided if the tumor is in or close to the mouth or esophagus.

[0216] AuroShell® particles are administered intravenously at a rate of 2 ml per minute for the first 15 minutes of infusion, increasing to a maximum of 10 ml per minute for the remainder of the infusion. Blood samples are taken at 0.5, 2, 4, 8, 24 and 48 hours to determine blood clearance of AuroShell® particles.

[0217] Vasoconstrictors should be avoided for the first 6 hours after administration to maximize efficacy. The first group of 5 patients will receive an intravenous infusion of 4.5ml / Kg of AuroShell® particles concentrated to 100 optical density (approximately 1.3x10^12 particles / Kg or 20mg particles / Kg). The AuroShell® dosage can be increased from 4.5ml / Kg to 7.5ml / Kg (or approximately 2.1x10^12 particles / Kg or 34mg particles / Kg) of AuroShell® particles concentrated to 100 optical density for groups 2 and 3 if no significant unanticipated device side effects related to the AuroShell® dosage are observed in group 1.

[0218] Laser Applications Calibration of the AuroLase® System and confirmation of proper operation can be performed prior to initiating laser treatment and is summarized below. Based on MRI, CT or similar imaging techniques, the tumor area can be mapped by the surgeon into a grid, allowing systematic laser irradiation of areas up to 1.0 cm outside the estimated tumor margin. This technique allows for the measurement of the estimated 1 cm per laser irradiation. 3The amount of tissue to be treated can be based on the amount of tissue to be treated. At 12-36 hours after AuroShell® injection, the patient is ready for treatment. At the physician's discretion, the patient can be sedated or anesthetized. The laser and cooling pump are connected with an interlock cable. The optical fiber is connected to the laser and threaded through the catheter. A sterile saline bag (1 liter) is hung and connected to the laser fiber cooling tubing set. The laser fiber cooling tubing is threaded through the peristaltic cooling pump and connected to the inlet port of the catheter. A drain tube can be connected to the outlet port of the catheter and connected to a liquid collection bag. The cooling pump is turned on and the cooling line is aspirated. The laser settings are adjusted to obtain the desired average power. The fiber power can be confirmed by inserting the catheter into a sterile tube attached to an integrating sphere photometer. The laser power knob can be adjusted to obtain the specified average power. The interstitial catheter can be placed proximal (within about 1 cm) of the tumor to be treated with a 14-gauge introducer catheter sheath to avoid tumor seeding. The laser is inserted through the catheter sheath, which can then be engaged with the introducer probe. The laser is fired for a set period of time, and then the fiber is repositioned (or a new introducer is inserted if the grid coordinates are to be changed). Using a 1 cm long 18 gauge Tru-Cut needle biopsy or similar procedure, a biopsy can be performed to obtain at least 6 mg of tumor tissue and gold accumulation can be measured by neutron activation analysis immediately after irradiating the patient with the laser. If multiple tumors are being treated in a single patient, biopsies need only be performed on odd numbered lesions (1st, 3rd, 5th, etc.).

[0219] Endpoints Up to five index lesions are identified for each patient. Index lesions are lesions that can be directly examined (e.g., by fiberoptic nasopharyngoscope or laryngoscope) and biopsied. They must also be able to provide at least 6 mg of tumor tissue via biopsy (1 cm long 18-gauge Tru-Cut needle biopsy or similar technique) for evaluation by neutron activation analysis. Tumor size is assessed from physical measurements and imaging techniques appropriate to the lesion, such as CT, MRI, or X-ray. Baseline measurements are taken immediately prior to AuroLase® treatment whenever possible. All measurable lesions, up to a maximum of five lesions, are identified as target lesions and recorded measurements are taken at baseline. Target lesions are selected based on their size (lesion with longest diameter) and suitability for accurate repeated measurement (imaging technique or clinical measurement). The sum of the longest diameters (LD) of all target lesions is calculated and reported as the baseline total LD. The baseline total LD ​​is the standard for objective tumor characterization.

[0220] All other lesions (or lesion sites) will be identified as non-target lesions and recorded at baseline. Measurement of these lesions is not optionally required, but the presence or absence of each should be recorded during follow-up.

[0221] result Patients experience a 60-80% reduction in tumor size six months after treatment. In 15% of patients, the cancer is completely eradicated. In 40% of patients, no side effects are observed and normal prostate function is maintained.

[0222] Example 4 The following study describes results achieved using nanoparticles (AuroShell®) in an embodiment of a laser catheter assembly as described elsewhere herein.

[0223] A pilot study of AuroLase® therapy (e.g., use of nanoparticles and delivery via a laser catheter as described elsewhere herein) in 11 human subjects with head and neck cancer that cleared an FDA IDE has been completed and found no safety-related issues with either particle delivery or laser treatment.

[0224] Similarly, a pilot study of AuroLase® Therapy in 22 human subjects with biopsy-diagnosed prostate cancer found no serious adverse events with either particle delivery or laser treatment. In total, at the time of the study, 33 human subjects had received AuroShell® particle injections and 26 had additional associated laser treatments with no reported serious adverse events.

[0225] The preclinical safety of AuroShell® particles has been established in in vitro and in vivo animal studies. Proof-of-concept studies have been performed using systemic administration of particles to inoculated tumors in the brain, injected directly into the canine prostate, and to human prostate tumors grown stereotactically in mice.

[0226] With the basics of animal and human safety now established, the focus of this study is on As disclosed, the objective of the study was to determine the efficacy of treatment with nanoshells and subablative infrared irradiation of those nanoshells using a laser catheter. The treatment was performed on patients suffering from prostate disease in a pilot study of 22 patients. All 22 patients were injected with nanoshells at three different dosage levels. Fifteen of these patients also underwent subsequent laser procedures. In a separate study, an additional 13 patients were injected with nanoshells followed by localized laser ablation of tumor tissue under ultrasound guidance.

[0227] Although the study was designed and organized as a safety study, numerous whole prostate sections of variable quality were available for histopathological analysis, from which additional conclusions regarding treatment efficacy could be drawn.

[0228] The prostate study was conducted under the auspices of Mexico's Health Safety Commission COFEPRIS as an open-label, multicenter, single-dose pilot study of AuroLase® Therapy in the treatment of subjects with resectable primary prostate cancer. Only subjects scheduled for radical prostatectomy were enrolled. The study was divided into two groups: 1) Group 1, where AuroShell® particles were injected 1 day before the scheduled radical prostatectomy, and 2) Group 2, where AuroShell® particles were injected 1 day before the laser treatment and 5±1 days before the scheduled radical prostatectomy. Patients were followed for 6 months after particle injection, with regular checks of vital signs, hematology, blood chemistry, and urinalysis. In total, 7 subjects completed the study in Group 1 and 15 subjects completed the study in Group 2.

[0229] Prostate Results Between January 2011 and July 2012, 22 prostate cancer patients were enrolled in Mexico. Each of these patients was injected with clinical AuroShell® particles (nanoshells as disclosed elsewhere herein), and 15 of them underwent AuroLase® Therapy laser treatment. Apart from the safety results, the results led to two general conclusions: 1) the laser energy ranged from no observable thermal damage to producing thermal lesions up to 1 cm over a narrow range of power settings; and 2) nuclear activation analysis (NAA) showed enhanced accumulation of AuroShell® particles in prostate adenocarcinomas, in contrast to normal prostate tissue.

[0230] Adverse events One patient had an apparent allergic reaction to the infusion, but recovered with the infusion medication. One patient experienced a burning sensation in the upper abdomen, but no treatment was given and the patient recovered naturally. No adverse events were reported due to the laser treatment.

[0231] Implantation and laser irradiation All patients were injected with the same 7.5 mL / kg (100 OD) volume of particles. This was to meter the particle dose by body weight and therefore blood volume. Fifteen subjects in group 2 underwent laser treatment the day after injection. The fiber optic system was placed once in the cortex of each hemisphere of the prostate using a transrectal ultrasound probe. Adjustments to the position of the fiber optic catheter within each hemisphere were made based on the location with the highest Gleason score shown by needle biopsy. The aim of the laser treatment was to demonstrate the safety of the procedure by developing a laser dose that would ablate tumor tissue but not healthy prostate. Although this was a safety study, efficacy insights were established by varying the laser dose, based on the optimal laser dose, with 3.0W to 3.5W applied for 3 minutes at each site. A total of six patients were treated with 3.5W or less. During the laser treatment of 15 patients, this dose was gradually increased to 5.0 W for 3 min (3 patients) and then decreased to 4.5 W for 3 or 4 min at each treatment site (6 patients).

[0232] Limitations of the Mexico study and interpretation of the results Although the safety assessment was quite satisfactory, the Mexico Prostate Trial was limited in its ability to assess treatment efficacy in the following ways:

[0233] 1) The standard 12-punch biopsy used to diagnose and stage patients for the study did not provide an accurate mapping of the number, extent, or specific location of a patient's tumors.

[0234] 2) Available small, portable ultrasound systems, while sensitive enough to insert a laser catheter into the general area of ​​a particular prostate hemisphere, did not provide the millimeter-scale resolution to reliably place the laser catheter within or adjacent to the tumor.

[0235] 3) the logistics of immobilizing, amputating, implanting, transporting, evaluating, and reporting a case rarely provided timely enough information to adjust treatment parameters before the next case.

[0236] 4) The private clinic where the study was performed was able to provide whole-mount slides of discontinuous but incomplete sections of laser-treated prostate.

[0237] Figures 14A-14I show representative whole mount sections from the last 9 of the 15 laser treated patients (those treated with 3.5W or more; scale bar = 1 cm). These H&E sections (hematoxylin and eosin) show the spatial relationship between the tumor tissue 1001 and the fiber optic placement 1002 present in the prostate 1000, and any resulting zones of coagulation necrosis 1003. For patients 208 and 210-215, at least one laser fiber placement was within or adjacent to an area of ​​the tumor. In general, the 4.5W level of treatment produced coagulation necrosis that conformed to the tumor border but generally not in the normal gland, whereas the 5.0W level of treatment generally tended to produce thermal lesions. Additionally, note that in no cases was the prostate capsule destroyed by the area of ​​coagulation necrosis.

[0238] FIG. 14A shows 3 minutes of 4.4W with no damage to the normal gland. FIG. 14B shows 3 minutes of 4.4W with no damage to the normal gland. FIG. 14C shows 3 minutes of 5.0W with non-specific damage to the normal gland. FIG. 14D shows 3 minutes of 5.0W with no damage to the normal gland and non-specific damage around the carcinoma. FIG. 14E shows 4 minutes of 4.5W with damage areas consistent with the tumor border (1003) and no damage in the secondary areas (1002). FIG. 14F shows 4 minutes of 4.5W with no damage to the normal gland and no damage around the cancer. FIG. 14G shows 3 minutes of 4.5W with thermal lesions overlying the carcinoma and normal tissue and in the normal gland enhanced by hemorrhage (upper left area, 1003). Figure 14H shows thermal damage to a normal bleeding gland after 3 min of irradiation at 4.5 W. Figure 14I shows 3 min of irradiation at 5 W with thermal damage in a normal bleeding gland (area marked by arrow, 1003).

[0239] Figure 15 shows the relative accumulation of AuroShell® particles in representative samples taken from patients 210 and 211 (see Figures 14D and 14E) as determined by NAA. The selected samples differ considerably, as do the tumor grades as determined by Gleason scores, but there is clearly a greater accumulation of particles in the tumor tissue.

[0240] Concept of therapeutic efficacy verification The optical properties of tissue limit the depth of propagation of the light energy, thereby allowing true focal therapy. Heat generated from the energy source is diffuse and non-specific in nature. Thermal ablation heat can be propagated on the millimeter scale, but is not specific to tumor morphology. AuroShell® particles allow for more precisely localized conformal therapy, delivering tumor-specific damage on the millimeter scale. An MRI fusion imaging approach with ultrasound guidance based on a priori MRI fusion imaging should allow precise placement of fiber optic catheters within or adjacent to the index prostate lesion targeted for ablation.

[0241] Details to demonstrate treatment efficacy Particle-directed therapy can be very localized. Within a narrow range of laser power settings of 4.0–5.0 W / cm, photothermal therapy can thermally ablate particle-containing adenocarcinomas and BPH while sparing normal glandular tissue.

[0242] As a result of enhanced light absorption due to the presence of particles, AuroLase® Therapy can generate photothermal lesions by raising the target tissue temperature to 55-65°C over a 3-4 minute treatment time. Such a temperature profile produces areas of coagulation necrosis that regranulate and dissolve over several days, in contrast to heat-fixed lesions, which tend not to disappear while appearing viable on most histopathological examinations. The results of photothermal ablation are fully apparent within 48-72 hours after treatment and are observable by MRI.

[0243] Because particle accumulation is a function of neovasculature and not cell surface biomarkers of vascular or cell walls, AuroLase® Therapy can be administered immediately after (or prior to) chemotherapy or radiation therapy. There is currently no evidence that the efficacy of AuroLase® Therapy is affected by previous treatments.

[0244] overview Questions about safety have been addressed, both in terms of particle safety and laser radiation.

[0245] The integration of MRI fusion imaging and subsequent directional placement of a laser catheter is a means to establish the efficacy and usefulness of AuroLase® Therapy in the treatment of localized prostate disease and represents a logical next step in the utilization of AuroLase® Therapy. MRI-ultrasound fusion techniques are useful in addressing limitations identified in previous AuroLase® Therapy studies by allowing 1) pre-treatment target planning and 2) image-guided placement of the laser catheter in close proximity to the index lesion to be ablated.

[0246] Three-dimensional localization of the fiber-optic catheter within the prostate, coupled with near real-time thermal data (ideally MRTI), would allow for appropriate treatment output and longer or shorter treatment times to tailor focal ablation to the index lesion to be treated.

[0247] Studies with head and neck squamous cell carcinoma, canine melanoma, oral cancer, and canine and human prostate have demonstrated the focal nature of particle-directed photothermal energy. Incorporation of imaging modalities allows for precise focal treatment. Furthermore, the co-localization of particles with tumor tissue allows for focal ablation tailored to the targeted tumor.

[0248] The potential benefits of AuroLase® Therapy include highly selective and rapid destruction of tumors while minimizing damage to surrounding tissue, potentially curing tumors with minimal toxicity. Preclinical studies have demonstrated that AuroLase® Therapy is effective and has no detectable systemic toxicity.

[0249] In summary, various embodiments and examples of methods, systems, and devices for treating tumors have been disclosed. Although the methods, systems, and devices have been disclosed in the context of those embodiments and examples, those skilled in the art will understand that the disclosure extends beyond the specifically disclosed embodiments to other alternative embodiments and / or other uses of the embodiments, as well as certain modifications and equivalents thereof. For example, some embodiments of the method are configured to be used with other types of devices and systems. The disclosure also expressly contemplates that various features and aspects of the disclosed embodiments can be combined with or substituted for one another. Thus, the scope of the disclosure should not be limited by the specific disclosed embodiments described above, but should be determined only by a fair reading of the claims that may follow or be presented in the future.

Claims

1. A laser irradiation device assembly comprising: The main body, a probe extending distally from the body; a sheath connector; The body includes: a first fluid chamber; a first hub in fluid communication with the first fluid chamber, the first hub including a first fluid port and a fitting configured to engage a first coolant line; a second fluid chamber having a waveguide opening; a second hub in fluid communication with the second fluid chamber, the second hub including a second fluid port and a fitting configured to engage a second coolant line; a waveguide hub configured to provide access to the second fluid chamber of the body, to receive a waveguide, and to direct the waveguide through the second fluid chamber and the waveguide opening of the second fluid chamber; The probe comprises: an elongate probe member having a flexible outer wall defining a tubular cavity within the elongate probe, the outer wall defining a first lumen in fluid communication with the first fluid chamber, the flexible outer wall extending from a portion proximal to the body to a distal portion having a sealed tip; an inner tubular member extending distally from the body and within the tubular cavity, the inner tubular member defining a second lumen and including an exit opening disposed within a distal portion of the elongate probe member and configured to receive the waveguide when the waveguide is directed through the waveguide opening; a sheath connector configured to engage with a corresponding connector of the catheter sheath such that when the sheath connector is engaged with the connector of the catheter sheath, the catheter sheath at least partially covers the probe.

2. 2. The laser irradiation device assembly of claim 1, wherein the catheter sheath stabilizes the probe when the sheath connector is engaged with the connector sheath via the connector of the catheter sheath.

3. 2. The laser irradiation device assembly of claim 1, wherein when the sheath connector is engaged with the connector sheath via the connector of the catheter sheath, the catheter sheath reduces the incidence of kinking of the probe.

4. 2. The laser irradiation device assembly of claim 1, wherein when the sheath connector is engaged with the connector sheath via the connector of the catheter sheath, the laser irradiation device assembly is held by the probe in a horizontal position without kinking the probe.

5. 2. The laser applicator assembly of claim 1, wherein the sheath connector is circumferentially disposed about at least a portion of the elongated probe member.

6. 2. The laser irradiation device assembly of claim 1, wherein the sheath connector is connected to the body of the laser irradiation device assembly and / or is integrated with the body of the laser irradiation device assembly.

7. 2. The laser irradiation device assembly of claim 1, wherein the sheath connector is connected to and / or integral with the elongated probe member.

8. 2. The laser projection device assembly according to claim 1, wherein the probe has a scale.

9. 2. The laser applicator assembly of claim 1, wherein the sealed tip is a domed tip.

10. 10. The laser applicator assembly of claim 9, wherein the domed tip is transparent to visible wavelength light, infrared light, ultraviolet light, or a combination thereof.

11. 2. The laser applicator assembly of claim 1, wherein the first lumen of the probe is in fluid communication with the second lumen of the probe.

12. 2. The laser irradiation device assembly of claim 1, wherein the first chamber is in fluid communication with the second fluid chamber through the probe.

13. 12. A laser irradiation device assembly as described in claims 1 to 11, characterized in that the probe comprises a reservoir located between the sealed tip and the outlet opening of the inner tubular member, the reservoir configured to allow circulation and / or movement of fluid between the first and second lumens of the probe.

14. A laser irradiation device assembly comprising: The main body, A sheath connector; A probe; The probe includes an elongate probe member extending distally from the body and including a first lumen and a sealed end; a distally extending inner tubular member disposed within the first lumen of the introducer probe, the inner tubular member having a second lumen and terminating at an exit opening within the elongate probe; the first lumen is in fluid communication with the second lumen; The laser irradiation device assembly, characterized in that the sheath connector is configured to engage with a corresponding connector of a catheter sheath, and the catheter sheath is configured to at least partially cover the probe when connected to the sheath connector via the connector of the catheter sheath.

15. 15. The laser irradiation device assembly of claim 14, wherein the catheter sheath stabilizes the probe when the sheath connector is connected to the connector sheath via the connector of the catheter sheath.

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