Systems, Devices, and Methods for Target Tissue Treatment

Abstract

In some embodiments, a system and method for facilitating local therapy to tissue within the body are disclosed. An infrared laser pulse is locally transmitted via an optical fiber to a target tissue region within the body, and pulse conditions suitable for local tissue disruption and liquefaction are provided. This enables fine tissue disruption, tissue homogenization, and removal of blood vessels and interstitial fluid channels, and the distal tip of the optical fiber can reach the target tissue region along a desired surgical path without significant tissue deformation or damage. When such a pulse-emitting optical fiber penetrates tumor tissue, a decrease in interstitial fluid pressure facilitates drug injection into the tumor, reduces diffusion, and allows the drug to be localized within the tumor. Tumor destruction and subsequent drug delivery can be performed using an integrated optical and fluid delivery device.

Description

Technical Field

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 388,136, filed on July 11, 2022, entitled "SYSTEMS, DEVICES AND METHODS FOR TARGETED DRUG DELIVERY", the contents of which are hereby incorporated by reference in their entirety.

Background Art

[0002] The present disclosure relates to systems and methods for delivering local therapy to a target tissue region within the body.

[0003] There are multiple treatments for cancer. One of the most commonly used treatments is the use of anti-cancer agents in a procedure known as chemotherapy. Since it is difficult to inject drugs directly into the cancer site, these drugs are administered systemically. Due to this requirement, anti-cancer agents need to be taken up very selectively against rapidly dividing cells or other morphological features that are specific to cancer cells (or other diseased tissues) rather than normal cells.

[0004] Unfortunately, in solid tumors, several factors, such as limited local blood flow to the tumor, permeability of tumor blood vessels, structural barriers due to perivascular tumor cells and extracellular matrix, and intratumoral pressure, inhibit the uniform distribution of systemic drugs. These obstacles to the delivery of systemic agents to tumors can be understood from the local tumor environment and morphology shown in Figure 1 of Kobayashi et al. (Kobayashi H, Watanabe R, Choyke PL., "Improving Conventional Enhanced Permeability and Retention (EPR) Effects; What Is the Appropriate Target?", Theranostics 2014; 4(1):81-89. doi:10.7150 / thno.7193). Due to the influence of the local morphology and pressure of the tumor, the number of drugs that can successfully be delivered may be severely limited. Furthermore, even in the case of highly selective drugs, there are still significant problems with the side effects of chemotherapy. The quality of life of people undergoing chemotherapy is extremely poor, and in many cases, life support devices are required.

[0005] As shown in Figure 1A of Boeckelmann et al. (Clemens Boeckelmann & Udo Schumacher (2019): "Targeting tumor interstitial fluid pressure: will it yield novel successful therapies for solid tumors?, Expert Opinion on Therapeutic Targets, DOI: 10.1080 / 14728222.2019.1702974), in normal tissues, capillaries are covered by pericytes, and the surrounding stroma contains a loose extracellular matrix (ECM) produced by local fibroblasts and penetrated by lymphatic vessels. Hydrostatic pressure and colloid osmotic pressure represent opposing forces involved in filtration and extravascular fluid exchange. The net outward filtration pressure in the steady state is approximately 1 mmHg. The distribution of solute molecules by diffusion covers a distance up to 100 μm from the capillary (dashed line). Convection passes from the capillary through the stroma to the lymphatic vessel and is based on the positive pressure gradient between the capillary and the lymphatic vessel. Summary of the Invention Problems to be Solved by the Invention

[0006] However, as shown in Figure 1B of Boeckelmann et al., in tumor tissues, high interstitial fluid pressure (IFP) reverses the situation, increasing the overall pressure inside the tumor and ultimately hindering the convective-driven transport of solute molecules. The pressure gradient spreads from the center to the periphery, allowing for reverse fluid flow. This results in a decreasing gradient of oxygen (O2), nutrients, and drug uptake. IFP is a product of tumor vascular leakage, absence of lymphatic vessels, and a denser and stiffer ECM produced by cancer-associated fibroblasts (CAFs). Means for Solving the Problems

[0007] Systems and methods for facilitating local therapy of tissue within the body are disclosed. In some exemplary embodiments, infrared laser pulses are transmitted locally to a target tissue region within the body via an optical fiber, and pulse conditions are provided that are suitable for causing local tissue disruption and liquefaction, thereby enabling fine tissue disruption, tissue homogenization, removal of blood vessels and interstitial fluid channels, and allowing the distal tip of the optical fiber to reach the target tissue region along a preferred surgical path without significant tissue deformation or damage. When an optical fiber emitting such pulses penetrates tumor tissue, a decrease in interstitial fluid pressure facilitates the injection of drugs into the tumor, reducing diffusion and allowing the drug to be localized within the tumor. Tumor disruption and subsequent drug delivery can be performed using a device that integrates optical and fluid delivery.

[0008] Accordingly, in one aspect, a system is provided for performing local tissue disruption and liquefaction of a tissue region within the body. The system includes a pulsed infrared laser source configured to generate infrared laser pulses, an optical fiber optically coupled to the pulsed infrared laser source, the optical fiber being configured such that the infrared laser pulses are transmitted through the optical fiber to a distal tip of the optical fiber, a cannula configured to receive and mechanically support the optical fiber, the distal tip of the optical fiber being configured to extend at least to the distal end of the cannula to transmit the infrared laser pulses beyond the distal end of the cannula, a laser pulse transmission assembly having, a navigation system configured to guide during operation of the laser pulse transmission assembly to position the distal tip of the optical fiber proximal to a tissue region within the body, a control circuit operably coupled to the pulsed infrared laser source, and comprising, The control circuit is configured to perform an operation of controlling the pulsed infrared laser source to emit the infrared laser pulse having laser pulse characteristics during penetration of the body tissue region by the distal tip of the optical fiber, and the laser pulse characteristics are selected to have a wavelength such that absorption by the laser-irradiated tissue volume is mainly due to excitation of the vibration modes of one or more components of the laser-irradiated tissue volume, having a pulse duration shorter than a first duration required for heat diffusion from the laser-irradiated tissue volume and shorter than a second duration required for expansion of the laser-irradiated tissue volume by thermal driving, having a pulse fluence and a pulse duration that result in a peak pulse intensity below a threshold at which tissue destruction and liquefaction by ionization occur within the laser-irradiated tissue volume, the pulse fluence being high enough to cause local tissue destruction and liquefaction of the laser-irradiated tissue volume, The pulsed infrared laser source is controlled to facilitate local tissue destruction and liquefaction during penetration of the distal tip of the optical fiber into the body tissue region, avoid significant deformation of the body tissue region, and facilitate positioning of the distal tip within the body tissue region, a system.

[0009] In some implementations of the system, the control circuit is configured to control the pulsed infrared laser source to transmit the infrared laser pulse having the laser pulse characteristics to position the distal tip of the optical fiber proximal to the body tissue region during operation of the laser pulse transmission assembly, whereby local tissue adjacent to the distal tip of the optical fiber is destroyed while the distal tip of the optical fiber moves through the tissue toward the body tissue region, significant deformation of the tissue is avoided, and positioning of the distal tip proximal to the body tissue region is facilitated.

[0010] In some implementation examples of the system, the distal tip of the optical fiber is extendable beyond the distal end of the cannula to facilitate penetration of the body tissue region by the distal tip of the optical fiber.

[0011] In some implementation examples of the system, after the distal tip of the optical fiber is inserted into the body tissue region, the control circuit is further configured to control the pulsed infrared laser source to emit the infrared laser pulses at a reduced pulse fluence below the threshold of local tissue destruction and liquefaction, and the reduced pulse fluence is at a level high enough to perform thermotherapy within the body tissue region for inducing apoptosis.

[0012] In some implementation examples of the system, it further comprises an additional laser source optically coupled to the optical fiber and configured to generate laser energy suitable for providing thermotherapy to the body tissue region, and the control circuit is further configured to control the additional laser source to emit laser energy for inducing apoptosis within the body tissue region after the distal tip of the optical fiber is inserted into the body tissue region.

[0013] In some implementation examples of the system, it further comprises an optical detection system optically coupled to the optical fiber and configured to supply interrogation light energy to the tissue destroyed and liquefied by the infrared laser pulse and detect the light energy radiated in response by the destroyed and liquefied tissue.

[0014] In some implementation examples of the system, the laser pulse transmission assembly further comprises a liquid supply conduit in fluid communication with the distal end of the cannula, and the system further comprises a liquid supply pump configured to supply a liquid therapeutic agent to the liquid supply conduit. The control circuit is operably coupled to the liquid supply pump, and the control circuit is further configured to control the liquid supply pump to administer the liquid therapeutic agent within the body tissue region after the distal end of the cannula is inserted into the body tissue region.

[0015] The cannula may have a primary lumen through which the optical fiber is extendable, the liquid supply conduit is provided as a side lumen of the cannula, the side lumen intersects the primary lumen at an internal port located within the distal region of the cannula, and after the distal tip of the optical fiber has retracted to a position proximal to the internal port, the liquid therapeutic agent present within the liquid supply conduit is in flow communication with the primary lumen to administer the liquid therapeutic agent beyond the distal end of the cannula.

[0016] The control circuit may be configured to control the liquid supply pump to supply the liquid therapeutic agent into the body tissue region after pre-applying thermotherapy to the body tissue region.

[0017] In some implementations of the system, the liquid therapeutic agent includes a photosensitizer for photodynamic therapy, the system further includes a photodynamic excitation laser source optically coupled to the optical fiber, the photodynamic excitation laser source is configured to generate photodynamic laser energy suitable for causing photodynamic activation of the photosensitizer for photodynamic therapy, and the control circuit is further configured to control the photodynamic excitation laser source to emit the photodynamic laser energy for activating the photosensitizer for photodynamic therapy after the liquid therapeutic agent has been administered to the body tissue region.

[0018] In some implementation examples of the system, the laser pulse transmission assembly further comprises a micro-biopsy aspiration conduit in flow communication with the lumen of the cannula, the system further comprises a micro-biopsy aspiration pump configured to cause a pressure drop within the micro-biopsy aspiration conduit, the control circuit is operably coupled to the micro-biopsy aspiration pump, and the control circuit is further configured to control the micro-biopsy aspiration pump to aspirate the liquefied tissue sample within the lumen of the cannula after the distal end of the cannula is inserted into the body tissue region and the tissue within the body tissue region is locally destroyed and liquefied.

[0019] In some implementation examples of the system, the laser pulse transmission assembly further comprises an aspiration conduit in flow communication with the distal region of the cannula, the system further comprises an aspiration pump configured to cause a pressure drop within the aspiration conduit, the control circuit is operably coupled to the aspiration pump, and the control circuit is further configured to control the aspiration pump to aspirate the liquefied tissue within the aspiration conduit during local tissue destruction and liquefaction.

[0020] In some implementation examples of the system, the navigation system has an ultrasonic imaging system, and the ultrasonic imaging system is configured to display, on a user interface, the position of the distal tip of the optical fiber determined based on the detection of a photoacoustic signal generated at the distal tip during the transmission of an infrared laser pulse having the laser pulse characteristics.

[0021] In some implementation examples of the system, the distal region of the cannula is tapered such that the outer diameter of the cannula decreases in the distal direction toward the distal end of the cannula.

[0022] In some implementation examples of the system, the diameter of the cannula exceeds the diameter of the optical fiber by less than 10% of the diameter of the optical fiber at the distal end of the cannula.

[0023] In some implementation examples of the system, the distal end of the cannula is provided with an inclination.

[0024] In some implementation examples of the system, the distal tip of the optical fiber is provided with an inclination such that the infrared laser pulse is emitted at an angle oblique to the longitudinal axis of the optical fiber. The inclination angle of the optical fiber may be within 10% of the inclination angle of the distal end of the cannula.

[0025] In some implementation examples of the system, the optical fiber is rotatable with respect to the body tissue region, and the control circuit is further configured to control the pulsed infrared laser source during rotation of the optical fiber to emit the infrared laser pulse having the laser pulse characteristics after the distal tip of the optical fiber is inserted into the body tissue region, thereby facilitating local tissue destruction and liquefaction over an enlarged volume within the body tissue region.

[0026] In some implementation examples of the system, it further comprises steering means for steering one or both of the cannula and the optical fiber.

[0027] In some implementation examples of the system, the laser pulse transmission assembly comprises one or more additional optical fibers, the optical fiber and the one or more additional optical fibers form an optical fiber bundle, the optical fiber bundle is optically coupled to the pulsed infrared laser source, and the infrared laser pulse is transmitted through the optical fiber bundle to the distal end of the optical fiber bundle.

[0028] In some implementation examples of the system, at least two optical fibers of the optical fiber bundle have oblique distal tips configured to direct the infrared laser pulses in different directions.

[0029] In another aspect, a method for performing local tissue destruction and liquefaction of a tissue region within a body is provided, the method comprising: While extending the optical fiber within the body such that the distal tip of the optical fiber penetrates the tissue region within the body, transmitting, through the optical fiber, an infrared laser pulse having laser pulse characteristics, the laser pulse characteristics being: Having a wavelength selected such that absorption by the laser-irradiated tissue volume is primarily due to excitation of the vibrational modes of one or more components of the laser-irradiated tissue volume; Having a pulse duration shorter than a first duration required for heat diffusion from the laser-irradiated tissue volume and shorter than a second duration required for thermal-driven expansion of the laser-irradiated tissue volume; Having a pulse fluence and a pulse duration that result in a peak pulse intensity below a threshold at which tissue destruction and liquefaction by ionization occur within the laser-irradiated tissue volume; The pulse fluence being high enough to cause local tissue destruction and liquefaction of the laser-irradiated tissue volume; The infrared laser pulse causes local tissue destruction and liquefaction while the distal tip of the optical fiber penetrates the tissue region within the body, avoiding significant deformation of the tissue region within the body and facilitating positioning of the distal tip within the tissue region within the body.

[0030] Before penetrating the body tissue region, in order to position the distal tip of the optical fiber proximal to the body tissue region, an infrared laser pulse is transmitted during operation of the optical fiber, so that when the distal tip of the optical fiber is moved through tissue toward the body tissue region, the tissue adjacent to the distal tip of the optical fiber is locally destroyed, significant deformation of the tissue is avoided, and positioning of the distal tip proximal to the body tissue region is facilitated.

[0031] After the distal tip of the optical fiber is inserted into the body tissue region, additional infrared laser pulses with a low pulse fluence below the threshold of local tissue destruction and liquefaction are transmitted by the optical fiber, and the low pulse fluence is high enough to perform thermotherapy for inducing apoptosis within the body tissue region.

[0032] Furthermore, to induce apoptosis within the body tissue region, an additional laser source optically coupled to the optical fiber is employed to transmit laser energy suitable for providing thermotherapy to the body tissue region.

[0033] Furthermore, an optical detection system optically coupled to the optical fiber is employed to transmit interrogation light energy to the tissue destroyed and liquefied by the infrared laser pulse and detect the light energy radiated in response by the destroyed and liquefied tissue.

[0034] The distal tip of the optical fiber extends beyond the distal end of the cannula to facilitate penetration into the body tissue region.

[0035] The cannula may further comprise a liquid supply conduit in fluid communication with the distal end of the cannula, the liquid supply conduit being filled with a liquid therapeutic agent, and the method comprises, after penetrating the body tissue region at the distal tip of the optical fiber, extending the distal end of the cannula into the body tissue region, retracting the optical fiber into the cannula, and administering the liquid therapeutic agent into the body tissue region.

[0036] The cannula may include a primary lumen in which the optical fiber is extensible, the liquid supply conduit is provided as a side lumen of the cannula, the side lumen intersects the primary lumen at an internal port located within the distal region of the cannula, and after the distal tip of the optical fiber has retracted to a position proximal to the internal port, the liquid therapeutic agent present in the liquid supply conduit is in flow communication with the primary lumen in order to administer the liquid therapeutic agent beyond the distal end of the cannula.

[0037] The method may include performing thermotherapy on the in-vivo tissue region in advance and then supplying the liquid therapeutic agent into the in-vivo tissue region.

[0038] The liquid therapeutic agent includes a photosensitizer for photodynamic therapy, and the method further includes employing a photodynamic excitation laser source optically coupled to the optical fiber and transmitting photodynamic laser energy suitable for inducing photodynamic activation of the photosensitizer for photodynamic therapy.

[0039] After the distal tip of the optical fiber penetrates the in-vivo tissue region, extend the distal end of the cannula into the in-vivo tissue region, employ a pump to reduce the pressure within the lumen of the cannula, and aspirate the liquefied tissue sample.

[0040] The penetration of the in-vivo tissue region by the optical fiber is guided by an ultrasonic imaging system, the ultrasonic imaging system is configured to display the position of the distal tip of the optical fiber on a user interface, and the position is determined based on detection of a photoacoustic signal generated at the distal tip during transmission of the infrared laser pulse having the laser pulse characteristics.

[0041] The distal tip of the optical fiber is chamfered obliquely such that the infrared laser pulse is emitted at an oblique angle with respect to the longitudinal axis of the optical fiber.

[0042] After the distal tip of the optical fiber is inserted into the body tissue region, additional infrared laser pulses having laser pulse characteristics are irradiated during rotation of the optical fiber to facilitate local destruction and liquefaction over an enlarged volume within the body tissue region.

[0043] The body tissue region is a tumor.

[0044] The functional and advantageous aspects of the present disclosure can be further understood by referring to the following detailed description and the drawings.

Brief Description of the Drawings

[0045] Hereinafter, embodiments will be exemplarily described with reference to the drawings.

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Embodiments for Carrying Out the Invention

[0046] Various embodiments and aspects of the present disclosure will be described with reference to the details described below. The following description and drawings are illustrative of the present disclosure and should not be construed as limiting the present disclosure. To fully understand the various embodiments of the present disclosure, numerous specific details are described. However, in certain instances, well-known or conventional specific details are not described in order to briefly describe the embodiments of the present disclosure.

[0047] As used herein, the terms "comprises" and "comprising" are to be construed as inclusive and non-exclusive. Specifically, when used in the specification and claims, the terms "comprises" and "comprising" and their variations mean that the specified function, step, or component is included. These terms should not be construed as excluding the presence of other functions, steps, or components.

[0048] As used herein, the term "exemplary" means "serving as an example, instance, or illustration" and should not be construed as being preferred or advantageous over other configurations disclosed herein.

[0049] As used herein, the terms "about" and "approximately" mean covering the variations that may exist in the upper and lower limits of a range of values such as characteristics, parameters, dimensions, etc. Unless otherwise specified, the terms "about" and "approximately" mean plus or minus 25 percent or less.

[0050] Unless otherwise specified, a specified range or group is understood to be a shorthand for referring individually to each member of that range or group, as well as to all sub-ranges or sub-groups that may be contained therein, and sub-ranges or sub-groups therein, and unless otherwise specified, the present disclosure relates to and expressly incorporates each specific member and combination of the sub-ranges or sub-groups.

[0051] As used herein, the term "on the order of," when used in conjunction with an amount or parameter, refers to a range corresponding to approximately one-tenth to ten times that amount.

[0052] As explained above, anti-cancer drugs are generally designed for systemic or whole-body exposure to kill the primary cancer and the migratory cells that may lead to cancer metastasis. This allows the cancer mass to be 10 times more concentrated than other body tissues. 4 The contrast can be less than one-fold smaller, placing significant constraints on the design of drugs that act very specifically on rapidly dividing cancer cells. However, this high contrast is necessary to preferentially kill cancer cells over healthy cells, but the required contrast is not perfect, which often results in the acute and debilitating side effects associated with chemotherapy. New classes of drugs can be designed for rapid uptake rather than high selectivity for a particular cancer profile. The amount of drug action may be determined by the diffusivity of the drug to a particular tissue. Therefore, localized drug injection directly into the tumor is desirable, as it would provide targeted therapy and avoid the complications and limitations associated with traditional chemotherapy.

[0053] When the location of cancer is clearly identified, the success of the method of directly injecting an anticancer agent using a needle into the tumor site is limited by the high osmotic pressure associated with cancer tissue. As a result, as shown in Figure 1, it is not possible to selectively treat only cancer tissue, and a net outflow of the drug occurs. Furthermore, the uptake of the drug is further complicated by diffusion away from the cancer site. There is no conventional means to prevent the diffusion loss of the drug at the target site. The pressure gradient and the associated net diffusion process lead to a loss of the local concentration of the drug at the cancer site. There is competition between the uptake (time) and diffusion (seconds to minutes) of the drug from the cancer site. These two processes lead to a decrease in the drug uptake efficiency when using conventional means of delivering a cancer therapeutic agent to the injection site. Similar problems exist in the treatment of most local intraluminal diseases.

[0054] The problem is further exacerbated by the development of chemoimmunity. Even a powerful drug that acts selectively on a specific type of cancer may further affect the evolution of the morphology of cancer tissue, causing an increase in osmotic pressure and abnormal angiogenesis. As a result, as described above, a form of immunity to the action of the drug may occur. Therefore, the direct administration of the drug using a needle fails as a result of the large interstitial fluid pressure (IFP) that hinders the physical administration of the required dose to the cancer site.

[0055] These effects limit the drug dose that reaches the critical concentration (LD50 for cancer cells) required to achieve the intended function. When the drug is provided in a uniform distribution, the drug is selectively taken up by the targeted cancer site. However, the spatial gradient of diffusion at the cancer site hinders this condition. This effect occurs frequently and is due to the high degree of vascular abnormalities, increased osmotic pressure, and further changes in tissue morphology caused by the action of the drug itself. In fact, in some solid tumors, the osmotic pressure becomes very high, making it physically impossible to inject the drug with a normal needle size and pressure. This is simply a problem that the huge pressure gradient inherent in cancer tissue makes it impossible to reach the cancer position with the drug. As described above, even if site-selective delivery is possible, there is a problem that the drug becomes normal diffusion dispersion from that site. The present disclosure provides a solution to this diffusion problem in the morphology of both normal and cancer tissues.

[0056] Another problem in the direct injection of drugs into solid tumors is access to the tumor location. Large open surgeries cause significant trauma and are a factor limiting the number and frequency of treatments for solid tumors located in multiple different positions. The use of surgical intervention to remove cancer tissue is limited in scope due to significant trauma and loss of function to the surrounding tissue. Usually, the surgical procedures attempted to eradicate cancer are only one or a few times. Metastasis to multiple sites leads to stage 4 cancer where survival by surgery is impossible. In some cases, less invasive procedures that minimize the amount of tissue damage, such as needle aspiration and related delivery methods, are attempted.

[0057] However, the hollow needle that is mechanically inserted into the body can cause trauma due to the shearing force required to push the needle into the target tissue site, limiting the repetition of treatment. Furthermore, although a number of flexible guiding needles that pass through a curved entry path to reach a target in the body have been developed, they also lead to tissue damage along the entry wound (for example, Van de Berg, Nick J.; van Gerwen, Dennis J.; Dankelman, Jenny; van den Dobbelsteen, John J. (2014). "Design Choices in Needle Steering - A Review", Design Choices in Needle Steering - A Review. IEEE / ASME Transactions on Mechatronics, (), 1-12. doi:10.1109 / TMECH.2014.2365999).

[0058] Figure 3A shows the problems faced when attempting to penetrate tumor tissue 20 using a conventional cannula 110 having an obliquely cut tip (e.g., a needle) and reach the target position 25. Until the needle 110 is advanced until it first contacts the skin surface, the surface deforms, and when the needle penetrates the tissue surface, the surface locally caves in (depresses). Eventually, the elastic limit is reached and the tissue spreads to fit the needle. As the needle advances into the tissue, the surrounding tissue further deforms. As the needle advances towards the tumor and cuts a path through the tissue, cells move or are pushed away. The needle compresses and deforms the tissue as it travels towards the intended location within the tumor. The needle damages the tissue due to both shear force trauma from the insertion of the needle and tissue deformation. Particularly when the tissue heterogeneity is large, it becomes difficult to reach the target area.

[0059] When the needle contacts the tumor, it contacts at a position displaced from the planned position due to the deformation of the tumor and the deformation of the tissue around the tumor caused by the advancement of the needle. Further advancement of the needle causes further deformation of the tumor due to the resistance of the high interstitial fluid pressure of the tumor to the penetration of the needle into the tumor, preventing the distal tip of the cannula 110 from reaching the target position 25 within the tumor 20.

[0060] When the inventors of the present application attempted to solve the aforementioned problems related to the local delivery of treatment to the tumor site, they identified the following issues. 1) The need to guide an optical fiber into the tumor tissue to enable more accurate targeting of the tumor without inducing significant deformation of the tissue. 2) The ability to penetrate the tumor and overcome the interstitial fluid pressure to facilitate the delivery of the required amount of drug delivered as a solution or gas. And 3) The need to limit the diffusion of the drug from the cancer site after delivery in order to enable drug uptake. The inventors considered that the need to block diffusion from cancer tissue required a direct intervention to change the flow gradient that causes the high interstitial fluid pressure in cancer tissue. Therefore, the inventors searched for a solution to facilitate the local delivery of treatment targeting an in-vivo tissue region (e.g., a tumor or other histopathological region). Desirably, without causing significant trauma or deformation to adjacent tissues, by substantially affecting only the in-vivo tissue region, there may be a possibility of repeating this treatment multiple times without compromising the quality of life.

[0061] As will be described in detail below, the first and second problems may be overcome by using a pulsed (e.g., ps or ns) infrared laser that transmits pulses having characteristics that result in local tissue destruction and liquefaction. This enables penetration into the tumor tissue and the creation of a path inside the tumor that is much smaller than that by invasion with a mechanical injection needle, and can avoid significant deformation of the tissue usually associated with needle-based biopsy.

[0062] This approach provides access to the tumor site with much less trauma than conventional methods and can selectively accumulate and control energy only at the tumor site. This may be beneficial in reducing the pressure rise in the tumor and facilitating subsequent local administration of therapeutic agents into the tumor.

[0063] Accordingly, various exemplary embodiments of the present disclosure provide systems and methods that advantageously utilize optically based local tissue disruption and liquefaction to facilitate the direct delivery of local therapies to in vivo tissue regions (tissue regions within the body). As will be described in detail below, local tissue disruption and liquefaction can be achieved using a pulsed infrared laser configured to transmit pulses that selectively target vibration absorption within the tissue and delivered at an appropriate pulse duration and fluence. For example, the wavelength of the infrared laser pulse can be selected to target the vibration absorption of water and cause very local tissue disruption due to the extremely strong absorption of infrared light in the OH stretching vibration region. The 1 / e penetration depth of the absorption in the OH stretching vibration region is on the order of 1 to 10 microns, which is smaller than the dimensions of a single cell.

[0064] A pulsed infrared laser system configured for emitting laser pulses having pulse conditions suitable for performing tissue disruption according to the foregoing mechanisms and the conditions described in further detail below is hereinafter referred to as a "PIRL (pulsed infrared laser)" system. Similarly, an infrared laser pulse having a wavelength, pulse duration, and energy suitable for performing tissue disruption and liquefaction according to the foregoing mechanisms is hereinafter referred to as a "PIRL" pulse. It will be understood that PIRL pulses are not limited to picosecond pulses. This is because, as will be described below, at some wavelengths the preferred pulse duration can extend into the range of tens of nanoseconds.

[0065] Since the PIRL laser pulse is an infrared laser pulse short enough to drive tissue disruption and liquefaction much faster than the time scales associated with heat and acoustic propagation, damage due to heat and shock wave formation can be avoided. It is also long enough to avoid the effects of ionizing radiation due to plasma formation. The PIRL pulse is irradiated at a wavelength selected such that the absorption of the laser pulse by the tissue is mainly due to the excitation of the vibration modes of one or more components of the tissue such as water. Therefore, examples of suitable wavelength ranges for the PIRL laser pulse include 2.7 - 3.3 μm, 5.9 - 6.1 μm, and 1.8 - 2.0 μm. Future development of high-energy short-pulse laser sources will enable tissue disruption and liquefaction by PIRL by targeting the vibrational absorption of target molecules in the 2 - 20 μm range.

[0066] For example, the wavelength of the PIRL laser pulse can be selected to overlap or be in the vicinity of a strong peak in the vibrational spectrum of the tissue components, with little water used for energy supply, such as the CC-stretching region of collagen or the N-H stretching of amino acids in proteins. Such vibration modes quickly absorb electromagnetic radiation and can effectively localize optical energy in the micron-scale deep sections of the exposed tissue. In the case of water, the maximum absorption of the vibration mode occurs between approximately 2.7 - 3.33 μm, and the broad peak (10 cm -1 sup) in the absorption spectrum corresponds to the short lifetime of the OH stretching vibration mode of liquid water molecules, which relaxes between sub-picoseconds and picoseconds and activates the surroundings. The spectrum also shows resonance conditions between the OH stretching vibration and other vibration modes such as OH bending vibration and intermolecular vibration modes. Other absorption peaks, such as the peaks at approximately 1.9 μm or approximately 6 μm, can also be used instead, as will be explained in more detail below.

[0067] In various exemplary embodiments, when a tissue of a predetermined volume is irradiated with a PIRL pulse, the pulse duration is generated and emitted such that it is shorter than (i) the duration required for heat diffusion from the volume of the laser-irradiated tissue and (ii) the duration required for thermally-driven expansion of the volume of the laser-irradiated tissue. One skilled in the art can determine an appropriate pulse duration for a PIRL pulse for a given pulse wavelength and absorption depth in a tissue (e.g., a given type of tissue). Generally, for a given PIRL laser pulse wavelength selected according to the aforementioned criteria (absorption of the laser pulse by the tissue is mainly due to excitation of the vibration modes of one or more components of the tissue), appropriate PIRL pulse durations that satisfy the aforementioned criteria (i) and (ii) can be calculated using known properties of the tissue such as the absorption depth of the laser pulse, the heat diffusion constant, and the speed of sound. Alternatively, in addition to that, experiments can also be conducted to determine appropriate laser pulse durations that satisfy criteria (i) and (ii).

[0068] For example, when tissue is destroyed and liquefied with a 3 μm laser wavelength having an absorption depth of about 1 μm, the maximum value of the pulse duration is the ratio of the absorption depth to the speed of sound, 1730 m, i.e., t = a / v = 10 -6 m / 1.730x103 m / s = 5.78x10 -10 seconds, which is about 600 ps (e.g., Duck, F.A., Physical Properties of Tissue, Academic Press, London, 1990, and Duck, F.A., Propagation of Sound Through Tissue, in "The Safe Use of Ultrasound in Medical Diagnosis", ter Haar G and Duck, F.A, Eds., British Institute of Radiology, London, 2000, pp. 4-15).

[0069] Different tissue types (e.g., bone, brain, skin) have different absorption depths at specific wavelengths. Near the OH stretching band, the absorption of tissue is dominated by water. Generally, the absorption depth is deeper than that of pure water. At a wavelength of 2.95 μm, the absorption depth of pure water is close to 0.7 μm. Considering the difference between high and low water concentrations in tissue and other OH stretching modes within the tissue, the absorption depth at this wavelength can be approximately 1 - 2 μm. When the laser wavelength shifts to, for example, 2.75 μm, the absorption depth of light increases by about 3 times according to the change in the absorption spectrum of OH stretching. (See, for example, Diaci, J., J. Laser and Health Acad. 2012, 1 - 13 (2012).)

[0070] In another example, a 6 - μm laser wavelength with an absorption depth of about 100 μm is used to destroy and liquefy tissue. In this case, the pulse duration should be selected to be shorter than 100 μm / 1.753×10³ = 57 ns. Similarly, when the laser wavelength is 1940 nm, the absorption depth is expected to be 100 μm. Therefore, the appropriate pulse duration of the PIRL pulse will depend on the pulse wavelength. In some implementation examples, the appropriate pulse duration of the PIRL pulse can range from 100 ps to 100 ns according to the selected wavelength and the intensity - dependent change in the absorption depth due to saturation of absorption at a given wavelength.

[0071] The pulse duration and pulse fluence are also selected to result in a peak pulse intensity below the threshold for ionization - driven ablation to occur within the volume of the laser - irradiated tissue. For example, for a given pulse duration, an upper limit value of the appropriate pulse fluence to avoid ionization - driven ablation may be determined. For example, in the case of human skin tissue, at a laser wavelength of 3 μm, when the pulse duration is 10 ps, 500 ps, and 1 ns, the maximum fluence values to avoid ionization - driven ablation are, as shown in Figure 2, approximately 1.5 J / cm 2 、5.5 J / cm 2 、17 J / cm 2 respectively.

[0072] Furthermore, to achieve PIRL-based tissue disruption and liquefaction with laser pulses that meet the aforementioned criteria regarding wavelength, pulse duration, and pulse fluence, a pulse fluence sufficient to achieve the threshold energy density for PIRL tissue disruption and liquefaction should be imparted to the laser pulses, as indicated by, for example, the tissue disruption and liquefaction threshold shown in FIG. 2. For example, the pulse fluence delivered to the tissue should be high enough such that the energy accumulated in the irradiated volume is sufficient to heat the contents of that volume to the evaporation temperature, including the enthalpy of evaporation.

[0073] For example, when the beam is focused to 200 μm (or used in contact with a fiber having a core diameter of 200 μm) and ablates a volume of approximately 1 μm × π(100 μm) 2 the mass of the ablated volume is 3.1x10 -8 g for water and 3.4x10 3 g for skin (density 1.15 g / cm -8 ). The energy required to raise the temperature of this volume of water from 20°C to 100°C and then evaporate that volume is approximately 80 μJ, which corresponds to a fluence of 0.25 J / cm 2 for a 200 μm spot. This fluence defines the threshold for instantaneous heat accumulation to drive the phase transition without losses outside the excitation zone due to acoustic propagation or heat diffusion. Since the incident intensity is effectively reduced in highly scattering media such as tissue, typical excitation conditions commonly used are 1 J / cm 2 . The determination of the fluence sufficient for tissue disruption and liquefaction by PIRL can be done experimentally by varying the applied fluence, examining the resulting tissue disruption and liquefaction, and selecting the applied fluence value that yields a sufficient amount or degree of tissue disruption and liquefaction. The subsequent process within the limited volume defined by the non-excited tissue and the fiber tip leads to tissue disruption at the cellular level and the removal of the pressure gradient.

[0074] In this implementation of the delivery of the PIRL pulse in contact mode, local tissue disruption / liquefaction occurs, enabling the optical fiber to advance without substantial shear friction (similar to a hot knife for butter). This enables fine tissue disruption, tissue homogenization, and removal of blood vessels and interstitial fluid channels. In this direct contact implementation, the optical fiber closes the space and confines the energy. Unlike resection-type PIRL that uses a non-contact mode to facilitate evaporation, in contact-type PIRL, the energy is not converted into translational motion as an ablation plume with material removal. Instead, the energy liquefies the solid material and leads to homogeneous nucleation involved in a phase transition that exceeds the barrier for forming bubbles from the lowest vapor pressure component. Without intending to be limited to theory, the inventors believe that the nucleation process and bubble formation occur in a spatially uniform manner corresponding to the energy distribution accumulated in the tissue by the thermal motion due to the rapid conversion of the absorbed infrared radiation. These nucleation sites coalesce over a longer time (more than 10 - 100 nanoseconds) to generate shock waves. This process is very locally limited by the initial homogeneous nucleation occurring in the PIRL process. Ultrasonic imaging has shown that these homogeneously generated nucleation sites are very effective in intentionally disrupting the tissue and dispersing the tissue very finely. This process effectively liquefies the tissue. Furthermore, this process is locally cumulative. By intentionally controlling the number of pulses, additional energy can be fed into the exposed volume to achieve thermal destruction and increase the volume of tissue destruction. Thus, in some embodiments, it is possible to use pulse trains of different lengths to increase the volume of tissue destruction in a controlled manner, extend the tissue destruction beyond the single-pulse limit of tens of microns, and control the degree of tissue heating as desired.

[0075] When a PIRL pulse is delivered to a local tissue region in the body through an optical fiber inserted into the body, local tissue destruction and tissue liquefaction occur, enabling the distal tip of the optical fiber to be guided into the tissue region of interest in the body without damage and accurately, and facilitating the direct entry of the distal tip of the optical fiber into a selected tissue region in the body such as a tumor or other regions related to pathology.

[0076] The beneficial properties of the transmission of the PIRL pulse by the optical fiber are shown in FIG. 3B. In this figure, a cannula 110 is interfaced with a pulsed infrared laser source and shows a state of accommodating an optical fiber 120 that delivers a PIRL pulse from its distal tip 122. The PIRL pulse destroys local cell structures and causes local tissue destruction and liquefaction in the volume of the laser-irradiated tissue beyond the distal tip of the optical fiber. Thereby, the optical fiber can be advanced substantially along a straight path without applying a force that causes deformation to the surrounding tissue.

[0077] As shown in the figure, the delivery of the PIRL pulse by the optical fiber facilitates the initial penetration into the tissue. This causes local tissue destruction and liquefaction without causing significant resistance, indentation, or deformation on the tissue surface when the distal tip advances into the tissue. Therefore, the optical fiber punctures the tissue surface with significantly less force and friction than the conventional method shown in FIG. 3A. The destroyed cells are pushed out behind the distal portion of the optical fiber in liquid form. The figure shows an example where the optical fiber extends from the distal end of the cannula during penetration, insertion, and movement of the tissue by PIRL mediation. In an alternative implementation, during penetration, insertion, and movement of the tissue by PIRL mediation, the distal tip of the optical fiber may be positioned adjacent to the distal end of the cannula 110, and the PIRL pulse may be caused to liquefy the tissue in the direct path of the distal end of the cannula.

[0078] As shown in FIG. 3B, at least the proximal portion of the optical fiber may be housed within a cannula to mechanically support the optical fiber when guiding it within the body. When a cannula is used to guide the optical fiber within the body, the cannula preferably has an outer diameter that is only slightly greater (e.g., less than 5%, less than 10%, less than 15%, less than 20%, or less than 25% of the diameter of the optical fiber) than the diameter of the optical fiber, at least in the distal region of the cannula. This additional thickness of the cannula is to prevent substantial tissue trauma when the cannula advances within the body. In some exemplary embodiments, the diameter of the cannula tapers distally towards the distal opening such that the cannula advances through the tissue with minimal resistance while reducing friction and allowing the laser to "clear obstacles".

[0079] As shown in FIG. 3B, due to tissue disruption and the resulting fluid flow characteristics, the fiber can advance to the tumor with little or no appreciable frictional or shear adhesion forces. This property enables a clear trajectory path to the tumor site without significant deformation of the tissue, ensuring access to the target tissue or region of interest. As will be explained in more detail below, this property of the fiber transmitting infrared laser pulses enables the injection of therapeutic agents without significant damage to the tissue along the entry path to the target site and ensures access to the target site without significant deformation of the tissue.

[0080] FIG. 3B also shows that due to tissue disruption and liquefaction by PIRL pulses emitted from the distal tip of the optical fiber, the distal tip of the optical fiber can penetrate into the tumor 20 without significant resistance and without being significantly deflected. As a result, the PIRL pulses emitted from the optical fiber facilitate the direct and unobstructed entry of the optical fiber into the tumor 20 without significant deformation of the tumor, enabling the distal tip of the optical fiber to be positioned at the desired in-tumor location 25.

[0081] The PIRL pulses delivered within the tumor reduce the barrier to the free flow of interstitial fluid into the hypoxic portions of the solid part of the tumor. The local disruption of tumor tissue caused by infrared laser pulses is conceptually similar to local high-energy radiation therapy using focused gamma rays or high-energy X-ray radiation (e.g., "gamma knife" or "cyber knife" techniques) to produce a local surge of ionization at the selected site. In such systems, large and costly equipment such as particle accelerators are required to obtain the desired radiation, and such methods operate based on a probabilistic model for the formation of ionization spikes. In contrast, the systems and methods of the present disclosure can be implemented using a compact and relatively low-cost benchtop laser with an optical fiber for transmitting laser energy, effectively forming a "tunnel" to the target site identified from preoperative images.

[0082] In some exemplary embodiments of the present disclosure, a thin rigid or flexible cannula is employed to facilitate the insertion and guidance of the optical fiber into the body. In other embodiments, the fiber may be employed to access the tissue region within the body and provide local treatment in the absence of a support cannula. The emission of the PIRL pulses and the disruption and liquefaction of the tissue present ahead of the distal tip of the optical fiber facilitate non-invasive fiber delivery and accurate fiber positioning. In fact, in cases where the optical fiber is guided without using a cannula, the size of the wound is slightly larger than the diameter of the fiber, for example, on the order of 50 to 200 microns in diameter. Since the size of the disruption filament is small and the non-thermal disruption mechanism is used, the damage to the tissue along the path towards the final target within the body is minimized.

[0083] In some implementation examples, the optical fiber can be inserted into the body by about 5 cm without mechanical support by a cannula (e.g., extended from the cannula or inserted without a cannula) without a significant risk of soft tissue damage. The optical fiber can be extended to this depth by controlling the advancement of the optical fiber at a low laser repetition rate, such as 10 to 100 Hz. This allows the optical fiber to be advanced without causing damage due to heat accumulation. Around the optical fiber, it is expected that the harder tissue structure will deform, but if the movement of the fiber is too fast, resistance will occur and the fiber may be damaged. With a penetration depth of 5 cm, most parts of the body can be accessed. If this depth is increased to 10 cm or more, it is expected that while aspirating the destroyed / liquefied tissue, the tissue can be further perforated deeper using a cannula or direct vision laser perforation method, enabling access to any part of the body.

[0084] For harder structures such as collagen and ligaments that interfere with the path to the tissue of interest, a small access hole can be formed using another laser (combining the laser energy from another laser and transmitting it through the same optical fiber). Examples of suitable lasers include excimer lasers and neodymium-based lasers at 266 nm, which can be employed for path formation. In such cases, by incorporating means to remove the destroyed tissue, it may be possible to reduce the accumulation of non-uniform stress and obstacle factors that lead to fiber breakage.

[0085] For example, in an implementation example where a cannula is employed for fiber support, the cannula (or other support structure) can be inserted into the body to a depth close to the body surface or to a position beneath the surface where damage is minimized. Thereafter, the optical fiber can be carefully advanced or retracted, the material aspirated to reduce the retraction resistance, and the optical fiber further advanced beyond the cleaning point. This procedure can be carried out intermittently, for example, every 5 mm of advancement of the optical fiber (it will be understood that the distance between aspiration events varies depending on the tissue). In many cases, due to local tissue disruption and liquefaction by PIRL pulses, it is expected that the tissue liquefies sufficiently such that the liquefied tissue can pass longitudinally along the outer surface of the fiber or cannula when advancing the optical fiber into the body.

[0086] In some embodiments, unlike previous endoscopic approaches that necessarily involve dimensions significantly exceeding 1 mm, one or more optical fibers (e.g., an optical fiber bundle) may be employed to facilitate an endoscopic pulsed infrared laser beam delivery device having a distal cross-sectional dimension of less than 1 mm. For example, as will be described in more detail below, in some implementation examples, for beam transmission to minimize damage to tissue along the entry path, the diameter of the distal region of the probe may be less than 300 microns, or less than 200 microns. The use of optical fibers is beneficial for the transmission of infrared laser pulses in both minimizing the invasion path to the target tissue and the removal of the target tissue.

[0087] Various embodiments of the present disclosure are thus employed to solve the problem of cancer removal without causing significant trauma, thereby enabling the removal of detectable cancer in the body even when the cancer has metastasized. Conventional cancer treatments often stop at stage 4 where metastasis has occurred because the risks of invasive surgery are excessive and surgical intervention is no longer an option. Embodiments of the present disclosure provide a novel means of supplying energy to access the region of interest without causing shear damage to the surrounding tissue. Multiple surgeries can be performed on stage 4 patients without causing trauma, and also to remove multiple cancers and to increase the efficiency of drug delivery.

[0088] In the optical fiber transmission of the PIRL pulse, the entrance-stage wound is on the order of 10 to 20 cells in diameter, and without shear damage, the wound is closed by the elastic repulsion of the tissue. This enables it to act without causing significant damage to the entry path to the target tissue to be removed. In contrast, in the case of a needle, a shear force is generated during insertion, which causes inflammation around the entry path. This action is involved in some of the actions and advantages resulting from acupuncture treatment. Furthermore, due to differences in actions and adhesiveness involved in the shear force, surface adhesiveness, and variations in tissue hardness, the needle deviates from the target site, making it difficult to place the needle accurately. In many cases, it is necessary to try the needle multiple times to statistically improve the probability of docking the needle at the desired site.

[0089] Embodiments of the present disclosure facilitate the insertion of a fiber-optic-based probe having a distal cross-sectional dimension on the order of sub-millimeters, which is significantly smaller than that of a needle therapy needle. Due to the action of PIRL guided within the optical fiber and the resulting tissue interaction, the insertion action of the optical fiber forms its own path without significant secondary damage or excessive shear forces and reaches the target site directly without tissue deformation or deviation of the path. This enables insertion along a desired or surgically essential path into any part of the body without leaving a scar. This process is likened to "passing a hot knife through butter," but the reconstruction of the local tissue (the butter in this analogy) and changes due to shear forces are minimal (in some cases virtually zero). As a result, the wound heals without forming scar tissue, minimizing the trauma to the body to enable the removal of diseased tissue. This function enables multiple surgeries in any procedure without imposing risks or excessive trauma on the patient. In particular, it has important applications in the removal of solid tumors in patients, which can expand and improve the quality of life of the patient.

[0090] Current approaches to minimally invasive surgical interventions, such as manual / robotic endoscopic surgery and laparoscopic surgery, can be performed using surgical navigation (guidance) methods, but the cross-sectional dimensions of such devices are still relatively large, and the trocar size typically ranges from 8.5 mm to 12 mm. In such invasive methods, especially when penetrating soft tissue, shear forces cause local damage and inflammation, usually resulting in damage even if the healing of the invasive wound is not debilitating.

[0091] The path of the optical fiber to this site can be tracked in real time while minimizing tissue deformation during passage, thereby ensuring an absolute orientation to the target tissue or precise location. In some implementation examples, a probe assembly including an optical fiber and a cannula (in some cases, an optical fiber without a support cannula) can be induced and adjusted in real time using one or more imaging methods such as, but not limited to, ultrasonic imaging, magnetic resonance imaging, fluoroscopy, computed tomography, angiography, electromagnetic position sensing, etc. Optionally, one or more detectable markers present on the cannula and / or optical fiber are employed, and optionally, surgical guidance based on intraoperative volumetric image data rendered in an intraoperative reference frame and presented on a user interface is also provided.

[0092] In some exemplary embodiments, the tip of the optical fiber can be detected and identified by ultrasonic imaging of the photoacoustic signal generated by local disruption of tissue by a PIRL pulse. For example, ultrasonic imaging may be employed to detect shock waves that enable the location of the distal tip of the optical fiber to be identified. Such embodiments can be beneficial in providing an improvement in positioning accuracy over what can be achieved based on detection of ultrasonic echoes from the tip region of a sapphire optical fiber, since ultrasonic artifacts can occur due to high reflectivity resulting from an acoustic property difference of 10 (v_sapphire = 10 times the speed of sound in water and more than 10 times the speed of sound in tissue). This is because at the boundary from high reflectivity to low reflectivity, structural interference occurs that can impair visualization of the exact position of the tip. By combining ultrasonic imaging and photoacoustic imaging, the active region in the distal end region of the fiber can be imaged with high precision. If ultrasonic imaging is performed at a sufficiently high frequency, in some cases, imaging of cancerous tissue is also possible due to an increase in angiogenesis within the tumor region. For example, the projection of the acoustic signal generated by PIRL tissue disruption, enhanced by phase difference and contrast agents (bubbles or nanoparticles) in the ultrasonic image, facilitates accurate positioning of the fiber and provision of appropriate treatment to the tissue of interest as intraoperative guidance.

[0093] The use of ultrasonic imaging is limited in depth resolution by acoustic attenuation that varies quadratically with frequency. To obtain sufficient spatial resolution to image the position of the fiber, current transducer technology benefits from an ultrasonic wavelength of approximately 30 MHz (or an acoustic wavelength of approximately 30 microns) to achieve a resolution close to the diffraction limit. At this frequency, the depth that can be imaged is limited to approximately 1 - 2 cm. This depth can be extended to approximately 5 cm by using lower frequencies, such as frequencies of 10 - 20 MHz.

[0094] To perform accurate position tracking and guidance at deeper positions within a body cavity, other imaging methods with lower contrast may be employed to identify the position of the fiber within the 3D space of the body cavity. For example, fluoroscopic X-ray images, use of electromagnetic field gradients, or MRI may be used for fiber imaging and position guidance. Such imaging methods may not have sufficient contrast to identify the relative position of the fiber with respect to important components within the body and to guide the fiber along an optimal surgical path.

[0095] In such cases, similar to the general features in imaging the fiber within the body, the large strain field generated by the PIRL process at the fiber tip can be utilized to uniquely determine the position of the distal tip. The effect of PIRL in tissue ablation by ultra-fast thermal energy accumulation in 10-micron units is a strain field (delta V / V) of 10 -2This leads to the above-described thermally-driven volume expansion. This strain field is orders of magnitude larger than the strain field emitted by the piezoelectric transducers used in ultrasonic imaging. This extremely large strain can be detected by conventional photoacoustic detection and serves as a very bright acoustic point source or beacon for uniquely positioning the fibers within the body. The extremely large scale of the strain field means that signals can be detected up to a depth of 5 - 10 cm or more, thereby enabling accurate photoacoustic identification of the position of the fibers anywhere within the body. This acoustic beacon is essentially generated by the action of the PIRL pulses emitted from the fibers to create a path by disrupting the tissue or to intentionally disrupt the tissue to cause apoptosis by heat. This acoustic beacon can be overlaid on other previously generated images such as CT scans or MRIs, or a position sensing device (e.g., the electrostatic position at the fiber tip) can be used. In the latter case, a pickup coil can be used to map and display the position of the fiber compared to a 3D CT scan or other pre-operative reference volume image (when the pre-operative image can be represented in the intraoperative reference frame, e.g., through the use of a stereotactic patient tracking device such as an optical tracking system or through intraoperative image fusion such as the fusion of ultrasound and CT images). The photoacoustic signal beacon provides a means for identifying the position of the tip of the optical fiber and the relationship of that position to the planned surgical path to the tissue of interest.

[0096] When the distal end of the optical fiber is positioned within a region of tissue of interest within the body, such as a tumor, the optical fiber may be used to transmit PIRL pulses having sufficient energy to destroy a desired volume of tissue, for example, via one or more pulses, and may be used at time intervals suitable to achieve destruction of the desired volume of tissue and / or ablation of a specific tissue volume as needed. For example, after reaching the target site using a laser fluence appropriate to penetrate the tissue, the energy and / or output of the infrared laser pulse can be increased to accelerate tissue destruction at the tip, and the tip can be scanned to eradicate the diseased tissue to increase the volume of destruction at the tumor site.

[0097] One of ordinary skill in the art will understand that experiments using actual or simulated tissue (e.g., phantom) should be conducted to achieve appropriate levels of PIRL-based disruption and / or liquefaction, and / or thermotherapy-induced apoptosis, and to determine appropriate pulse energy, number of pulses, and / or pulse repetition frequency. For example, when PIRL pulses tuned to the water resonance of OH stretching are irradiated at a wavelength of 2.7 - 3.3 μm, it has been found that the profile from about 10 - 100 microns deep from the fiber exit surface (depending on the selected wavelength and the mechanical properties of the tissue) is disrupted and liquefied by the interaction of each pulse exceeding the tissue disruption threshold.

[0098] Due to tissue deformation and liquefaction by PIRL, when the optical fiber penetrates the tissue region of interest, heat diffusion from the tip position of the optical fiber can be utilized within a defined volume element to cause thermally induced apoptosis. The optical fiber can be placed at the desired position of the target tissue and energy can be transmitted using heat diffusion. For example, continue irradiating the PIRL laser or use a WDM fiber system to absorb energy through other absorption bands (e.g., the absorption band of hemoglobin in blood) at other wavelengths, such as light at 532 nm (green), heat the tissue to apoptosis, and achieve a clearly defined killing zone for eradicating cancer cells and other diseased tissues.

[0099] Tissue necrosis can be achieved by programmed temperature changes (delta T) within a controlled zone. Known power can be applied to kill the tissue by heating the tissue and raising the temperature of the desired boundary, for example, up to 60 °C. At this temperature, cells undergo "programmed cell death" or apoptosis. In most applications, a simple diffusion model can be used to accurately determine the required power and irradiation time to induce apoptosis of cells up to the desired tissue diameter. There are various designs for optical temperature sensors, including fluorescence monitoring, phase coherence monitoring, or reflectivity measurements including Bragg gratings written at the tip of an optical fiber, which can be incorporated at the distal end of the waveguide. The optical temperature sensor can ensure an appropriate irradiation protocol to induce apoptosis over the desired tissue volume by monitoring the local temperature in situ during photothermal irradiation.

[0100] FIG. 4 shows an example of a system for PIRL-based local tissue destruction and thermotherapy. The optical fiber 120 transmits PIRL pulses from the PIRL laser system 130 to the probe body 100. The PIRL pulses may be coupled from the laser source to the optical fiber 120 via a coupling 140 (which may be a rotary optical joint that facilitates rotation of the optical fiber with respect to the PIRL laser system 130. Alternatively, an optical rotary joint may be housed within or on the probe body 100). An additional light source 182 capable of emitting laser energy suitable for intratumoral thermotherapy (heat-mediated apoptosis) is coupled to the optical fiber 120 via, for example, a fiber optic coupler 142 and a wavelength division multiplexing coupler 144. In some exemplary embodiments, the optical fiber is provided within an assembly that includes a support enclosure (probe body and cannula) in multiple sections and is extendable therefrom. In some cases, the fiber itself may be encapsulated within a metal or plastic cannula that is located within a larger metal cannula (nested probe assembly). The fiber may protrude a certain distance from the final section of this assembly, depending on the thickness and coating of the fiber.

[0101] As shown, the optical fiber 120 is received and supported by the probe body 100. The distal cannula 110 extends from the distal end 102 of the probe body. In some implementations, the distal portion of the optical fiber 120 is located at or near the distal end of the cannula 110 or is extendable relative to the distal end of the cannula. In other implementations, the distal cannula 110 supports a distal optical waveguide that is optically communicated with the distal end of the optical fiber 120. It will be appreciated that the optical fiber 120 may be formed from two or more segments. In some implementations, at least a portion (e.g., the distal portion) of the cannula 110 is flexible.

[0102] The distal cannula 110 is angled and positioned by the operator (or via the robotic surgery subsystem) and advanced directly to the target tissue 20. This is facilitated by PIRL-based tissue disruption and liquefaction, minimizing secondary damage to adjacent tissue along the path to the target tissue 20. Initial angle adjustment is provided by the distal cannula portion 110 with an accurately determined initial position at the entry point into the body and a forward trajectory to the target tissue, with the assistance of an image and / or positioning subsystem (i.e., a “navigation” or “guidance” system) 150 that includes geometric position and delivery. The PIRL pulse is used to facilitate penetration of the tumor by the distal tip of the optical fiber. After positioning the distal tip of the optical fiber at the desired location, the second laser source 182 is controlled to perform thermotherapy, and, optionally, the distal tip of the optical fiber is repositioned to different locations within the tumor during delivery of the thermotherapy.

[0103] Although the illustrated implementation example shows the use of ultrasound-based image guidance, any suitable image guidance system, tracking system, or positioning system may be employed to facilitate targeting of the probe, and optionally, surgical guidance based on intraoperative volumetric image data rendered in the surgical reference frame and displayed on the user interface may also be provided.

[0104] As shown, the system for direct drug injection into a tumor or cavity includes a PIRL laser system 130 coupled to an optical fiber such that the output at the distal end of the optical fiber has conditions (wavelength, pulse duration, and intensity as described above) sufficient to facilitate very local micro-disruption of the tissue.

[0105] As described above, the position of the optical fiber 120, i.e., the distal optical waveguide, or the distal region of the cannula 110, is detected by a surgical guidance or navigation system and may optionally be displayed relative to pre-operative image data. The surgical guidance or navigation system includes a manual or motorized positioning mechanism that guides the insertion of the distal end of the device and inserts it into the body towards the target tissue volume (destroyed tissue) to be destroyed by the laser within the boundaries of the solid tumor target. The position of the distal end of the optical fiber, distal waveguide, and / or cannula can be determined, for example, by using a combination of spatial images such as ultrasound, X-ray, MRI, and a position sensor.

[0106] FIG. 5 shows the delivery of hyperthermia within tumor 20 via the same optical fiber 120 used to achieve access into the tumor by delivery of PIRL laser pulses. After positioning the distal tip of the optical fiber within the tumor by access into the tumor via PIRL, a second laser (e.g., laser system 182 of FIG. 4) is used for the transmission of hyperthermia.

[0107] Taking into account heat diffusion, the wavelength of the second laser can be selected based on the desired length of heat accumulation. For example, a near-infrared 750 nm CW laser that absorbs up to a depth of about 5 mm in tissue, or a green laser such as 550 nm that absorbs up to a depth of about 0.5 mm in tissue can be employed. In some implementations, a laser with an output of 532 nm is used to accumulate energy in the target tissue by light absorption of oxygen transport dyes such as hemoglobin and myoglobin so that it is preferentially absorbed by the cancer tissue in cancer tissue with developed blood vessels. Also, considering heat diffusion, the adjustable wavelength can be adjusted to regulate the absorption depth in order to heat the target tissue to the temperature desired for apoptosis at an optimal heating rate and more efficiently target the cancer tissue.

[0108] As shown in FIG. 5, for example, in accordance with a surgical plan, it is possible to reposition and / or redirect the distal tip of the optical fiber during the performance of thermotherapy in order to supply a desired spatial distribution and amount of thermal energy. For example, preoperative volumetric image data for estimating the size of a tumor, and the known or estimated thermal conduction and diffusion transport characteristics of the tumor, the known or estimated absorption depth of a second laser for a given absorption band, and a set of positions and directions for ensuring the temperature increase necessary to achieve apoptosis at a given time interval and laser irradiation dose are used to determine the system that can use this information.

[0109] In some embodiments, an optical fiber transmission system transmits pulsed infrared light pulses and provides an infusion path for a liquid therapeutic agent (e.g., a drug), minimizing secondary damage to adjacent tissue while enabling tissue disruption at the fiber exit, thereby creating a pressure gradient common to highly vascularized cancerous tissue that leads to drug efflux and loss of efficacy and a path for drug delivery.

[0110] Some exemplary embodiments of the present disclosure facilitate the local infusion of a liquid therapeutic agent (e.g., a drug) to improve the effectiveness of injectable drugs for tumor destruction and other medical procedures, for example, beyond what is deliverable with a normal needle. For example, embodiments of the present disclosure can address the problem of chemoresistance due to the presence of high interstitial fluid pressure, reduce pressure by tissue disruption, and facilitate the uniform dispersion of the drug at a specific target site for optimal drug delivery. Thus, some exemplary embodiments of the present disclosure can be employed, for example, to reduce by orders of magnitude the amount of drug required to selectively attack cancerous tissue, thereby facilitating the reduction of side effects of chemotherapy. Thus, the method may potentially lead to an improvement in the quality of life approaching a pre-cancerous state by reducing the side effects associated with chemotherapy. In some exemplary embodiments, after drug delivery, it is possible to create a barrier to the physical diffusion of the drug from the cancer site by the application of radiation or energy delivery, thereby potentially further enhancing the effect.

[0111] Accordingly, in some aspects, the present disclosure provides means for facilitating the selective delivery of a liquid therapeutic agent to cancer tissue, even to highly osmotic tissues, and blocking the diffusion of the liquid therapeutic agent away from the cancer site, thereby solving the problem of diffusion from the uptake target cancer site even under normal osmotic conditions. Further, in some aspects, the present disclosure additionally or alternatively facilitates the site-selective delivery of a liquid therapeutic agent or other substance to a predetermined location in the body without damaging the surrounding tissue in the drug delivery act. As described above, some aspects of the present disclosure enable subsequent blocking of diffusion from the injection site to solve both the problems of high osmotic pressure that blocks the drug from reaching the cancer site and diffusion from that site after injection. The methods of the present disclosure may avoid or reduce dependence on drug therapy by systemic administration by enabling access to cancer sites by site-selective drug delivery. This function can, for example, reduce the required dose by orders of magnitude, thereby avoiding the side effects associated with chemotherapy.

[0112] Such embodiments of the present disclosure can be employed to avoid or reduce the need for highly selective drugs as currently required according to current standard treatment methods that rely on systemic treatment. Instead, for example, it can be combined with means for delivering a drug suitable for rapid local uptake and subsequently blocking further diffusion by forming a barrier to diffusion transport from the drug delivery point as needed. The ability to directly and locally target tumor cells while they are present within the tumor may potentially obviate the need to also target mobile cancer cells that lead to cancer metastasis.

[0113] Figures 6A and 6B schematically show the direct injection of drugs into tumors via tissue disruption by an initial pulsed infrared laser pulse. In step A, the fiber optic needle disrupts the zone of solid tumor tissue, thereby reducing the interstitial fluid pressure by perforation / contraction. As shown in Figure 6B (step B), the drug is then injected under lower pressure, whereby the drug maintains a state of being localized within the tumor with less diffusion. The process shown in Figures 6A and 6B is carried out in two steps: the initial delivery of the pulsed infrared laser pulse via a first optical delivery device and the subsequent injection of the drug into the optically disrupted tumor via a second drug injection device. In another implementation example, the optical disruption of the tumor and the subsequent delivery of the drug are carried out using a single integrated optical and fluid delivery device, as will be described in more detail below.

[0114] The above-mentioned third challenge, i.e., the need to avoid the diffusion of the therapeutic drug injected into the tumor, can be addressed by selecting special compounds or by additionally combining the activation of photoactivatable compounds. For example, the same laser transmission fiber is used to transmit an additional light source specifically designed to be optimal for drug interactions or photoadhesion to the tumor. Additional radiation can be applied at an appropriate wavelength, pulse duration, and interaction time to cause local photoactivation of the drug. The drug can be specifically modified for the purpose of photoinduced fixation (a reaction state is generated in which the protecting group is photodecomposed to physically fix the drug to the cancer site). For example, in some implementation examples, chemotherapeutic drugs can be employed along with means to physically fix the drug or to enhance uptake faster than diffusion from the cancer site.

[0115] Due to the tissue destruction and liquefaction mechanism of PIRL, excessive shear forces when the device enters the tissue are avoided, and the wound entry trauma is significantly reduced, enabling rapid healing. In the case of fiber delivery, the cross-sectional wound is the size of the fiber itself. By tapering the tip of the fiber, it can be reduced to an order of 200 microns in diameter or less, down to about several tens of microns, which is approximately the same size as a single cell and smaller than any acupuncture needle. Here, a pulsed infrared laser output from the distal tip of the device eliminates the need to apply mechanical force. Therefore, a fiber configured to transmit infrared pulses can be inserted anywhere in the body with minimal damage. As described above, when the fiber exits the tissue, the tissue elastically rebounds, and without causing shear damage to the tissue, the size of the wound can be reduced to the diameter of about 10 - 20 cells, leaving only minimal damage.

[0116] The elimination or significant reduction of this trauma means that this approach can be considered for use even in metastatic cancer because there is no or minimal additional penalty for the patient regarding recovery. In conventional cancer surgery, a large incision involving extensive destruction and mechanical movement of healthy tissue is required to reach the cancer site. According to the exemplary method of the present disclosure, there is substantially no limit to the number of procedures that can be performed as long as the cancer can be imaged to determine its spatial location. Such an approach makes it practical to physically retain the drug within the cancer site by intentionally causing tissue damage through drug binding that photoactivates a blocker specific to the cancer treatment drug locally and enhancing the barrier that prevents the drug from diffusing from the target site. Also, if necessary, it is possible to deliver photothermal energy to achieve conditions much higher than those inducing heat denaturation such as coagulation or cauterization (ventilation).

[0117] Accordingly, in some exemplary embodiments, a probe is provided that includes an optical fiber for transmitting infrared laser pulses and a fluid delivery conduit for delivering a drug. Referring now to FIG. 7, an exemplary system is shown for performing tissue destruction of a PIRL-based tumor and subsequent drug delivery to the destroyed tumor. Similar to the exemplary system shown in FIG. 4, a hand-held probe body 100 having a proximal end 101 and a distal end 102 is shown in this figure. The optical fiber 120 transmits PIRL pulses from the PIRL laser system 130 to the probe body 100. The PIRL pulses may be coupled from the laser source to the optical fiber 120 via a coupling 140 (which may be a rotary optical joint to facilitate rotation of the optical fiber with respect to the PIRL laser system 130. Alternatively, an optical rotary joint may be housed within or on the probe body 100).

[0118] As shown, the optical fiber 120 is received and supported by the probe body 100. The distal cannula 110 extends from the distal end 102 of the probe body. In some implementations, the distal portion of the optical fiber 120 is located at or near the distal end of the cannula 110 or is extendable relative to the distal end of the cannula. In other implementations, the distal cannula 110 supports a distal optical waveguide that is in optical communication with the distal end of the optical fiber 120. It will be appreciated that the optical fiber 120 may be formed from two or more segments and that at least the distal portion of the cannula 110 may be flexible.

[0119] The present example system for direct drug injection into a tumor or cavity comprises a PIRL laser system 130 coupled to an optical fiber. Thereby, the output at the distal end of the optical fiber has conditions (wavelength, pulse duration, and intensity as described above) sufficient to facilitate highly localized microdestruction of tissue, significantly reducing the interstitial fluid pressure and enabling direct local injection of a liquid therapeutic agent. As described above, the position of the optical fiber 120, the distal optical waveguide, or the distal region of the cannula 110 can be detected and displayed by a surgical guidance or navigation system in comparison with preoperative image data as needed.

[0120] FIG. 7 also shows an implementation example in which a fluid delivery conduit 165 supplies a drug or other fluid to the probe body 100. The fluid is supplied to the fluid delivery conduit 165 by a fluid source (e.g., a fluid reservoir) and a pump. In the implementation example shown in FIG. 7, the fluid is supplied to the fluid delivery conduit 165 by a syringe pump 170. The fluid delivery conduit 165 is interfaced with an internal lumen within the probe body 100 or extends therein, and the fluid within the fluid delivery conduit 165 can be administered from the distal end of the cannula 110 or from a fluid channel formed within an optical waveguide extending from or extensible from the distal end of the cannula 110. The syringe pump 170 controls the injection of a controlled dose of a pharmaceutical compound (drug) selected for the treatment of the tissue target.

[0121] In some exemplary embodiments, the system shown in FIG. 7 may include an additional laser source coupled to the optical fiber 120 and used for delivering optical energy for additional treatment. For example, it is used for performing local hyperthermia before or after injecting a therapeutic agent into a region of interest within the body. An example of such an extended system is shown in FIG. 14A and will be described in more detail below. For example, a dual therapy involving an initial local hyperthermia followed by delivery of a local therapeutic agent may be beneficial in that the local delivery of the therapeutic agent enhances the accumulation of laser energy and thermally kills cancer cells, and further, targets an anti-cancer agent therapy that increases the collection amount and has high selectivity for rapidly proliferating cancer cells, and preserves cell components to enable the reabsorption of cancer cells typically observed as tumor shrinkage. The latter effect provides two hammers to kill cancer with higher reliability, causes the cancer tissue to be reabsorbed, and leads to maximum recovery of tissue function without the dead tissue interfering with the function.

[0122] FIGS. 8A-8D show implementation examples of a cannula 110 having an integrated fluid channel (lumen) 200 and a stretchable optical fiber 120. At a position remote from the distal end (not shown), a port for insertion of the optical fiber 120 and for fluid communication to a fluid delivery conduit (shown in FIG. 7) is provided. As shown in FIGS. 8A-8C, the optical fiber 120 can be advanced into the target tumor tissue 20. For example, a pull-back or push-forward mechanism can be incorporated into the probe body or disposed proximal to the probe body (e.g., as shown in FIG. 14A) to facilitate the advancement and / or retraction of the optical fiber 120. As described above, the cannula 110 can be advanced into the tissue using a position sensing system and / or a guidance / navigation system. Also, if desired, a PIRL pulse can be delivered into the tissue during advancement of the cannula, thereby forming an entry wound that minimizes damage to the surrounding tissue.

[0123] When reaching within the boundary of the target tissue (e.g., tumor), the PIRL pulse is delivered, and as shown in FIG. 8B, while extending the distal end of the optical fiber 120 (or optical waveguide) into the target tissue, intratumoral destruction is caused within the target tumor. To facilitate intratumoral injection of the administered drug, the optical fiber 120 is retracted to a position behind the fluid channel junction 210 located within the cannula 110 primed with the drug prior to injection to avoid injection of air bubbles, as shown in FIG. 8C. By pulling the optical fiber 120 to a position proximal to the fluid channel branch portion, the fluid channel 200 is in fluid communication with the distal portion of the central lumen 220 of the cannula (the portion where the optical fiber 120 can extend), thereby opening a flow path between the fluid channel 200 and the distal port 230 of the cannula 110. Since the local microstructure of the tumor is destroyed, the drug is not only injected into the destroyed tissue volume but also injected into the interstitial fluid of the tissue with little resistance due to mechanical perturbation of the extracellular matrix. Thereby, the drug can further diffuse within the tumor and overcome the previously existing pressure gradient leading to outflow of the drug from the target site, as shown in FIG. 8D.

[0124] FIGS. 8A - 8D show a design example in which the drug is administered through the central lumen used for extension of the optical fiber 120 at the distal end of the cannula 110. However, it will be understood that other implementation examples can also change the design without departing from the scope intended by the present disclosure. For example, the fluid channel may extend to or be extendable from a port adjacent to the position where the distal end of the optical fiber exists at or near the distal end of the cannula. In another implementation example described in more detail below, the fluid conduit may be a lumen existing within the optical fiber itself.

[0125] It will be understood that the distal tip of the optical fiber (optical waveguide) may be tapered or cut obliquely. For example, FIG. 8A shows an optical fiber 120 having a distally cut tip 122 obliquely. FIGS. 8A-8D show exemplary embodiments in which a single optical fiber or optical waveguide is used for the transmission of PIRL pulses for tissue disruption, but it will be understood that the waveguide may be composed of multiple fibers (e.g., an optical fiber bundle). In some implementations, at least a portion of the optical fiber or optical waveguide may include fibers with different tilt angles, such as planar for advancing the fiber forward, or fibers cut at an angle for increasing lateral tissue disruption and radial removal of tissue.

[0126] Another example of such an embodiment is shown in FIG. 9, which shows an apparatus in which the distal tip 122 of the waveguide is angled, creating an asymmetry that results in an angular projection of the PIRL pulse. In some implementations, the deflection angle can be rotated about the central longitudinal axis of the fiber by rotation facilitated by having a rotary fiber optic joint provided at a location remote from the distal end of the optical fiber. In some implementations, by rotating while advancing the optical fiber, the total volume of tissue to be removed can be determined by the number of advancement steps and the number of rotations, and tissue can be selectively disrupted with an accuracy of 10 to 100 microns.

[0127] By advancing while rotating and combining with, for example, the asymmetric distal end of a fiber angled like a wedge, it becomes possible to selectively guide an optical fiber along any path with a minimum curvature determined by the lateral displacement caused by the asymmetric shape and direction of the laser output. An example of this angle control is shown in FIG. 10. This is a device for rotating and beam steering that rotates a single angled optical fiber 300, regardless of the presence or absence of assistance in the interaction between the laser and the tissue, to control the forward vector of the optical fiber, or to sequentially direct a laser pulse to one or more optical fibers, thereby controlling the vector of the interaction between the laser and the tissue, and showing a bundle 310 of angled optical fibers where the optical fiber preferably moves in other directions into the cavity of the destroyed tissue. Also, steering by conventional mechanical means using a shape memory metal deformed in advance, a metal whose shape is changed by heat, or opposing pull-in wires can be employed. The goal is for the optical end face of the delivery catheter to occupy the largest cross-sectional area with respect to the total diameter of the distal end in order to minimize friction.

[0128] FIG. 11 shows another exemplary embodiment in which the distal tip of the optical fiber includes a movable and / or deformable distal optical component shown as an angled waveguide tip 320 in the figure, and the angle of the distal optical component 320 can be remotely controlled by, for example, increasing the angular displacement of the advancing optical fiber in combination with mechanical deflection and / or the optomechanical effect of the transmitted laser pulse via the actuation of an adjustment wire or other mechanism.

[0129] FIG. 12 shows an exemplary embodiment including an end piece 340 that is movable (removable) to open a perfusion channel through which fluid flowing inside the hollow waveguide exits from the distal tip of the waveguide, where the optical waveguide is a hollow fiber 330, for example, a sapphire window / sphere / tip shape. In some implementations, a small mechanism such as a hinge or a set of tension wires is released to move the movable end piece 340 far enough from the tip to inject fluid from the distal end of the hollow fiber 330. The fluid flow through the distal opening of the hollow fiber 330 can be controlled by a mechanism such as a piezo valve arranged in series with the fluid channel, but is not limited thereto.

[0130] In some exemplary embodiments, when a fluidics element is coupled to a hollow fiber that shares a hollow channel to the tip, as shown in FIG. 13, gas and / or liquid can be injected into the waveguide channel to supply liquid and then the channel can be emptied for the transmission of laser pulses. Additional fluid channels can be integrated with additional control valves for suction, perfusion, pressure control within the channel, and priming of the channel with liquid.

[0131] In some embodiments, a plurality of optical fibers (and / or cannulas containing the optical fibers) may be used to treat an area of interest (e.g., a tumor), each optical fiber being inserted into the patient and directed towards the area of interest from respective angles and / or insertion positions. Each optical fiber may be interfaced with a PIRL laser source (using a plurality of PIRL light sources as needed, each PIRL light source transmitting optical pulses to respective subsets of one or more optical fibers). This allows each optical fiber to function independently and facilitates insertion and guidance into the area of interest with minimal damage by ensuring that local damage that occurs when moving the optical fiber into the tissue area does not cause collective damage to adjacent fibers. In other words, damage to each fiber can be minimized so that each fiber functions independently without the possibility of collective or non-linear increased effects. By inserting multiple fibers at different angles and causing tissue damage through interaction with multiple shock wavefronts and / or accumulation and thermal diffusion of thermal energy, it is possible to remove substantially any volume of tissue. In the latter procedure, even relatively large cancers the size of a golf ball, which are usually only detectable by current imaging diagnostics for early cancer detection, can be treated.

[0132] From the above description, this type of tumor can be induced to undergo apoptosis without the risk of physical movement or unintended metastasis of cancer cells by heating the tumor volume to a desired diameter with an appropriate irradiation time by laser heating and subsequently killing the cancer cells by site-selective drug delivery. Site-selective drug delivery can eradicate cancer with a much lower dosage than conventional drug therapies, enable resorption of the cancer tissue, and restore tissue function as observed by reduction of the cancer volume as much as possible.

[0133] In some exemplary embodiments, a hollow fiber waveguide may be employed to direct a PIRL pulse for tissue disruption to form a drug delivery pathway. The hollow fiber may comprise a tapered sapphire tip 400 that includes one or more perfusion channels 410, as shown in FIG. 13. The perfusion channels may be formed laterally along the sapphire tip such that each channel is in direct fluid contact with the internal hollow region of the fiber waveguide, thereby facilitating a continuous pathway for drug delivery within the hollow fiber after optical disruption by a laser pulse. Alternatively, the perfusion channels may be connected to another perfusion conduit defined within the lumen of the hollow fiber waveguide or within a sheath that houses the hollow fiber waveguide. Since the action of the PIRL pulse causes explosive heating with a force gradient that expels material in a direction perpendicular to the tip, it is believed that the channels will not be blocked by laser-driven tissue disruption and / or forward movement of the fiber. This action is expected to prevent debris from entering each perfusion channel, remove material that has entered the channel during aspiration by subsequent PIRL pulses, and further advance tissue disruption to move the fiber to the target site.

[0134] As described above, FIG. 13 shows a configuration example in which a sapphire end piece 400 is provided in the distal region of a hollow waveguide 330, and the sapphire end piece including one or more perfusion channels 410 is in fluid communication with the central lumen of the hollow waveguide. The figure shows an implementation example in which a plurality of perfusion channels are located on the tapered side surface. By using a photonic crystal or a hollow fiber, it may be possible to realize a compact and less disturbed fiber transmission solution. The end piece, preferably sapphire, is infrared transmissive and has sufficient hardness to withstand the laser-driven shock waves involved in tissue disruption following impulsive infrared pulse heating.

[0135] In an exemplary embodiment where the fiber is a photonic crystal fiber, the sapphire endpiece may include a perfusion channel having a proximal opening in fluid communication with the hollow holes of the photonic crystal / hollow fiber. Each proximal opening may have a diameter equal to or approximately equal to (e.g., within 5%, 10%, 15%, 20%, 25%) the diameter of the respective hollow hole. The sapphire tapered endpiece includes a perforation or channel and is fused to the hollow fiber or secured via an adapter plug that slightly increases (e.g., an increase of less than 5%, 10%, 15%, 20% or 25%) the diameter of the fiber delivery device.

[0136] As illustrated in FIG. 14A, in some exemplary embodiments, an additional light source 180 may be coupled to the optical waveguide for the purpose of photo-fixing the delivered drug compound to increase drug uptake and / or prevent rapid diffusion. In one example of such an implementation, the same distal tip shown can be used to return the optical fiber to the target and expose the volume of the injected drug to sufficient light radiation to obtain the desired photochemical result.

[0137] FIGS. 14B - 14G illustrate the mechanism of laser-assisted injection of a photodynamic drug, where the drug is designed for faster uptake than diffusion from the tumor boundary, and the drug is activated by an additional light source that resonates with the photodegradable group attached to the drug molecule, generating a photoadhesive that binds in place while generating singlet oxygen for the destruction of cancer cells. This latter step allows for continuous monitoring of tumor shrinkage, adjustment of the light dose as needed, and control of the singlet oxygen dosage to appropriately adjust cancer treatment.

[0138] FIG. 15 shows an exemplary embodiment where the distal end of the optical fiber is angled or tapered so that the fiber end can be translated and rotated to irradiate a larger volume of tissue either independently or simultaneously with additional PIRL irradiation. Such an implementation may facilitate irradiation of laser light with a wavelength, pulse duration, and duration of time suitable for modifying the area around the target site to prevent diffusion of the drug away from the target. This step may include, for example, but is not limited to, photoemission of removable groups on particulate drugs such as photodynamic therapy (PDT) drugs. This forms a chemical bond at the target site, i.e., the drug is blocked and fixed at the target site. In the case of photodynamic therapy, the action of the drug can be controlled by irradiating light using an optical fiber. The optical fiber can be the same one used for the initial destruction of the target tissue or another optical fiber using the same path. Another way to utilize light to block drug diffusion is to physically block diffusion by coagulating the surroundings or ablation by high-power irradiation, enabling real-time monitoring and treatment modification to reduce the volume of cancer or completely remove cancerous tissue.

[0139] In some implementations, as illustrated in FIG. 16, after drug delivery, the dosed drug solution may be irradiated with PIRL radiation to generate a photo-mechanical force that creates a large pressure gradient inside the tumor due to the photo-mechanical cavitation effect, improving drug diffusion.

[0140] In another exemplary embodiment, as shown in FIG. 17, an additional laser source is provided for photothermal treatment of the target tumor as described above.

[0141] In another exemplary embodiment, the above-described exemplary embodiment may be configured to obtain a micro-biopsy sample of the liquefied tissue.

[0142] In other exemplary embodiments, the optical fiber used for the transmission of the PIRL pulse may be connected to an external optical detection system configured to deliver interrogation light energy through the optical fiber to the disrupted and liquefied tissue and collect the light energy radiated in response from the disrupted and liquefied tissue. The disrupted and liquefied tissue may be present beyond the distal end of the cannula. Alternatively, after retracting the optical fiber to create a partial vacuum, the disrupted and liquefied tissue may be present within the distal portion of the cannula. By way of non-limiting example, methods for performing in-situ micro-biopsies include spectroscopic methods such as Raman spectroscopy, fluorescence spectroscopy, frequency combs, and laser-induced breakdown spectroscopy. For example, Raman spectroscopy can be performed by also using the optical fiber used for PIRL disruption for the transmission of excitation energy and the collection of backscattered Raman signals. This Raman signal can be analyzed for biomarkers of disease or normal tissue. Very high excitation and thermal heating of the tissue can also lead to optical emissions that are spectral features or fingerprints of specific components of the tissue. Such an approach may be employed, for example, to determine whether the distal tip of the optical fiber is within a target tumor (or other identifiable in-vivo tissue region), and such an analysis may be performed, for example, before, during, or after the administration of a particular local therapy.

[0143] In other exemplary embodiments, the fluid channels employed for the delivery of therapeutic agents, and / or additional fluid channels, can be placed in communication with a pump (e.g., a mechanical pump or a syringe). The pump can be controlled to aspirate one or more volumes of the disrupted and liquefied tissue for biopsy analysis. This biopsy aspiration step can be performed at any time before, during, or after the administration of a local therapy to a selected in-vivo tissue region.

[0144] In another exemplary embodiment, as shown in FIG. 18, for long-duration photodynamic therapy (PDT), one or more optical fibers inserted into a subject via a PDT light source may remain in place even after the infusion procedure.

[0145] In another exemplary embodiment, the optical fiber can include an optical pressure sensor for continuous measurement of IFP, which can be a useful biomarker for the evolution of the tumor microenvironment and response to treatment, as shown in FIG. 19.

[0146] In another exemplary embodiment, the system is configured such that tumor tissue destroyed by contact with the laser-excited fiber tip is intentionally released around the tumor by flushing or aspirating the tissue out of the tumor and reinjecting it outside the tumor by pulling the needle or other means. The reinjection involves injecting into the vasculature such that the destroyed tissue contains tumor-specific antigens that are not damaged or denatured during destruction, creating an abscopal effect. This system can be deployed independently or in combination with, for example, drugs that activate the immune system, immune checkpoint inhibitors, T cells, macrophages, dendritic cells, and innate immune regulators.

[0147] FIG. 20 shows an example of a system for performing PIRL-based local tissue destruction and direct local drug injection into the destroyed tissue. The PIRL laser pulse is generated by a PIRL laser source 130 and transmitted through an optical fiber 120 that passes through a probe body 100 (handpiece) having a distal cannula region 110, and the optical fiber 120 can be extendable from the distal end of the cannula 110 as needed. The figure shows a state where the insertable cannula 110 is inserted into a subject, the distal portion of the optical fiber 120 is extended and irradiates the tissue region 20, and the tissue is being destroyed.

[0148] The laser source 130 can be operably coupled or connected to the control and processing hardware 500 for its control. Exemplary control and processing hardware 500 may include a processor 510, a memory 515, a system bus 505, one or more input / output devices 520, and a communication interface 525, as well as a plurality of optional additional devices such as an external storage 530 and a data acquisition interface 535. In one implementation example, a display (not shown) may be employed to provide an input for facilitating the control of the operation of the system 500. The display may be directly integrated into the control and processing device (e.g., as an embedded display) or provided as an external device (e.g., an external monitor).

[0149] The storage container 175 contains a fluid therapeutic agent (e.g., a drug compound, a medicine), and the action of the pump 170 controlled by the control and processing system 500 achieves the delivery of the drug to the tissue region through the probe body 100.

[0150] The position sensing and guidance of the cannula 110 and the distal optical fiber 120 (or optical waveguide) are facilitated by a position sensing subsystem 150 interfaced with the control and processing system 500.

[0151] The figure also shows that an additional laser source optically coupled to the optical fiber 120 or the distal optical waveguide (e.g., via a wavelength multiplexing device or an optical coupler) may be included as needed. This is for delivering in additional forms of optical radiation, such as a laser source suitable for photo-fixation, photodynamic therapy, and / or photothermal ablation or heat-driven apoptosis.

[0152] The control and processing system 500 may include, or be connectable to, a console 190 that provides an interface for an operator to easily control the laser source 160. The console may include, for example, one or more input devices such as a keypad, mouse, joystick, touch screen, etc., but is not limited thereto, and may include a display device as needed.

[0153] The methods described herein, for example, the operation sequence of local PIRL-based laser ablation and the subsequent control method of fluid delivery, the method of controlling the extension and retraction of the optical fiber as needed, and / or the method of controlling one or more valves fluidly connected to the pump and / or storage container, and other exemplary methods described below, etc., can be implemented via the processor 510 and / or the memory 515. As shown in FIG. 20, the executable instructions represented as the control module 550 are processed by the control and processing hardware 500. Such executable instructions may be stored, for example, in the memory 515 and / or other internal storage.

[0154] The methods described herein can be partially implemented via the hardware logic of the processor 510 and partially implemented using the instructions stored in the memory 515. Some embodiments can be implemented using the processor 510 without using additional instructions stored in the memory 515. Some embodiments are implemented using the instructions stored in the memory 515 for execution by one or more microprocessors. Accordingly, the present disclosure is not limited to a particular configuration of hardware and / or software.

[0155] It should be understood that the exemplary systems shown in the figures are not intended to be limited to the components that may be employed in a particular implementation. For example, the system may include one or more additional processors. Further, one or more components of the control and processing hardware 500 may be provided as external components interfaced to the processing device. Further, although the bus 505 is depicted as a single connection between all components, it will be understood that the bus 505 may represent one or more circuits, devices, or communication channels that link two or more of the components. For example, the bus 505 may include a motherboard. The control and processing hardware 500 may include more or fewer components than those shown.

[0156] Some aspects of the present disclosure can be embodied, at least in part, in software, which when executed on a computing system, transforms a general-purpose computing system into a special-purpose computing system capable of executing the methods disclosed herein or variations thereof. That is, a processor, such as a microprocessor, can execute a series of instructions included in a memory, such as ROM, volatile RAM, non-volatile memory, cache, magnetic disk, optical disk, or remote storage device, to implement these techniques in a computer system or other data processing system. Further, these instructions can be downloaded to a computing device via a data network as a compiled and linked version. Alternatively, the logic for performing the above processes can also be implemented in additional computer and / or machine-readable media, such as large-scale integrated circuits (LSIs), application-specific integrated circuits (ASICs), electrically erasable programmable read-only memories (EEPROMs), field-programmable gate arrays (FPGAs), and discrete hardware components.

[0157] A computer-readable storage medium can be used to store software and data that, when executed in a data processing system, cause the system to perform various methods. The executable software and data can be stored in various locations, such as, for example, ROM, volatile RAM, non-volatile memory, and / or cache. Portions of this software and / or data can be stored in any of these storage devices. As used herein, the terms "computer-readable material" and "computer-readable storage medium" refer to all computer-readable media per se, excluding a transitory propagated signal itself.

[0158] The exemplary embodiments described above can be used in a wide range of clinical applications. It will be understood that the foregoing exemplary therapeutic applications, including direct injection into tumors and local chemotherapy, are merely examples of implementations and are not intended to limit the scope of the present disclosure. It will also be understood that the exemplary embodiments can be employed in other wide-ranging applications, such as, for example, site-specific drug therapy or local delivery of fluids to tissues other than cancerous tissue for micro-biopsies for the detection of cancer or other disease states.

[0159] In some implementation examples, the embodiments of the examples disclosed herein may be employed for intracranial applications including, but not limited to, local chemotherapy, neuromodulation, and nerve stimulation of brain metastases. For example, the advancement of a PIRL-based probe (e.g., an optical fiber or probe that houses an optical fiber for transmission of PIRL pulses or other optical waveguides) can be employed to enter the brain with minimal secondary damage to the surrounding tissue by destruction and liquefaction of the PIRL-based tissue along the entry path with minimal secondary damage. Such minimally invasive PIRL-based probes can be employed for the treatment of intracranial lesions, for example, by tissue destruction and liquefaction and / or heat treatment. Probes configured to facilitate both tissue destruction and liquefaction by PIRL and local fluid delivery, such as the above-described embodiments or variations thereof, can be employed to facilitate non-invasive entry into the brain and subsequent local delivery of therapeutic agents within the brain. Also, if desired, tissue destruction and liquefaction based on PIRL can be used in combination with heat treatment of internal tissues. In this case, the ability to reach the brain without tissue deformation, deviation from the optimal path to the region of interest, or secondary damage is extremely important for absolute minimally invasive procedures for brain tumors, lesions, biopsies, and drug delivery.

[0160] While many of the exemplary embodiments disclosed herein relate to the provision of local therapy to tumor tissue, these exemplary embodiments are not intended to be limited to the local treatment of tumor tissue. Instead, it will be understood that they can also be employed for the provision of local therapy to an in vivo tissue region or for providing internal access to in vivo tissue for any minimally invasive treatment method. For example, the method of this embodiment can be employed for the treatment of a wide range of pathologies associated with internal tissues. For example, defibrillation by local destruction of heart tissue, the onset of a heart attack, removal of tissue clamping a nerve involved in chronic pain without the complications of scar tissue formation such as re-injury to the nerve or recurrence of chronic pain, endovascular surgery, repair of blood vessels with internal bleeding such as cerebral infarction by thermocoagulation using a similar beam transmission method, removal of nasal or vocal cord polyps, creation of an opening for improving blood circulation, implants that require the formation of a cavity within tissue such as a microcochlear implant, benign tumors, certain autoimmune diseases, cardiovascular diseases characterized by arterial lipid deposition such as atherosclerosis, fibrotic diseases such as pulmonary fibrosis and cirrhosis, angioplasty, nerve tissue transection, restenosis where excessive tissue growth occurs after procedures such as plastic surgery, etc., but is not limited thereto. Example

[0161] The following examples are presented so that those skilled in the art can understand and implement the embodiments of the present disclosure. These should not be regarded as limiting the scope of the disclosure, but rather as merely exemplary and representative. Example 1: Demonstration of ultrasonic detection of the tip position of an optical fiber by detecting a photoacoustic signal during irradiation of a PIRL pulse

[0162] As shown in FIG. 21, an optical fiber was imaged using a Vevo 3100 high-resolution ultrasonic imaging system. The left image shows the ultrasonic image before irradiation of the PIRL pulse by the optical fiber. The right image was acquired while the optical fiber was emitting the PIRL pulse, and clearly shows the photoacoustic signal associated with PIRL-induced cavitation beyond the distal end of the optical fiber. The laser output was synchronized with the imaging system for the timing gate of the imaging ultrasonic signal and the photoacoustic signal generated by laser emission in the liquid.

[0163] The specific embodiments described above are shown by way of example, and it should be understood that these embodiments are susceptible to various modifications and alternative forms. Furthermore, it should be understood that the claims are not intended to be limited to the specific forms disclosed, but rather are intended to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the present disclosure.

Claims

1. A system for localized tissue destruction and liquefaction in the body's tissue region, A pulsed infrared laser source configured to generate infrared laser pulses, An optical fiber optically coupled to the pulsed infrared laser source, wherein the infrared laser pulse is transmitted through the optical fiber to the distal end of the optical fiber, A cannula configured to receive and mechanically support the optical fiber, wherein the distal end of the optical fiber can extend at least to the distal end of the cannula in order to transmit the infrared laser pulse beyond the distal end of the cannula, A laser pulse transmission assembly having, A navigation system configured to guide the distal tip of the optical fiber proximal to a region of internal tissue during operation of the laser pulse transmission assembly, A control circuit operably coupled to the pulsed infrared laser source, Equipped with, The control circuit is configured to control the pulsed infrared laser source to emit an infrared laser pulse having laser pulse characteristics while the distal tip of the optical fiber penetrates the body tissue region, the laser pulse characteristics having a wavelength selected such that absorption by the laser-irradiated tissue volume is mainly due to the excitation of vibrational modes of one or more components of the laser-irradiated tissue volume. The pulse duration is shorter than a first duration required for thermal diffusion from the laser-irradiated tissue volume, and shorter than a second duration required for thermally driven expansion of the laser-irradiated tissue volume. The pulse fluence and pulse duration have such that the peak pulse intensity is below the threshold at which tissue destruction and liquefaction due to ionization occurs within the laser-irradiated tissue volume, The pulse fluence is sufficiently high to cause localized tissue destruction and liquefaction of the laser-irradiated tissue volume. A system wherein the pulsed infrared laser source is controlled to facilitate local tissue disruption and liquefaction during the penetration of the distal tip of the optical fiber into the body tissue region, thereby avoiding significant deformation of the body tissue region and facilitating the positioning of the distal tip within the body tissue region.

2. The control circuit is configured to control the pulsed infrared laser source to transmit infrared laser pulses having the laser pulse characteristics in order to position the distal tip of the optical fiber proximal to the body tissue region during operation of the laser pulse transmission assembly, thereby locally destroying tissue adjacent to the distal tip of the optical fiber while the distal tip of the optical fiber moves through the tissue toward the body tissue region, thereby avoiding significant tissue deformation and facilitating the positioning of the distal tip proximal to the body tissue region, according to claim 1.

3. The system according to claim 1, wherein the distal end of the optical fiber is extendable beyond the distal end of the cannula to facilitate penetration of the internal tissue region by the distal end of the optical fiber.

4. The system according to any one of claims 1 to 3, wherein the control circuit is further configured to control the pulsed infrared laser source after the distal tip of the optical fiber has been inserted into the body tissue region, to emit the infrared laser pulses at a reduced pulse fluence below a threshold for local tissue destruction and liquefaction, the reduced pulse fluence being at a level sufficiently high to perform thermotherapy within the body tissue region to induce apoptosis.

5. The system according to any one of claims 1 to 3, further comprising an additional laser source optically coupled to the optical fiber and configured to generate laser energy suitable for providing thermotherapy to the tissue region, wherein the control circuit is further configured to control the additional laser source to emit laser energy for inducing apoptosis within the tissue region after the distal end of the optical fiber has been inserted into the tissue region.

6. The system according to any one of claims 1 to 3, further comprising an optical detection system optically coupled to the optical fiber and configured to supply investigative light energy to tissue destroyed and liquefied by the infrared laser pulse, and to detect the light energy emitted in response by the destroyed and liquefied tissue.

7. The laser pulse transmission assembly further comprises a liquid supply conduit that is in flow communication with the distal end of the cannula, The system further comprises a liquid supply pump configured to supply a liquid therapeutic agent to the liquid supply conduit, The system according to any one of claims 1 to 3, wherein the control circuit is operably coupled to the liquid supply pump, and the control circuit is further configured to control the liquid supply pump to deliver the liquid therapeutic agent within the tissue region after the distal end of the cannula has been inserted into the tissue region.

8. The system according to claim 7, wherein the cannula has a primary lumen from which the optical fiber can extend, the liquid supply conduit is provided as a side lumen of the cannula, the side lumen intersects the primary lumen at an internal port located in the distal region of the cannula, and the liquid therapeutic agent present in the liquid supply conduit flows into communication with the primary lumen in order to deliver the liquid therapeutic agent beyond the distal end of the cannula after the distal tip of the optical fiber has retracted to a position proximal to the internal port.

9. The system according to claim 7, wherein the control circuit is configured to control the liquid supply pump to supply the liquid therapeutic agent into the body tissue region after applying thermotherapy to the body tissue region in advance.

10. The system according to claim 7, wherein the liquid therapeutic agent comprises a photodynamic therapy agent, the system further comprises a photodynamic excitation laser source optically coupled to the optical fiber, the photodynamic excitation laser source is configured to generate photodynamic laser energy suitable for causing photodynamic activation of the photodynamic therapy agent, and the control circuit is further configured to control the photodynamic excitation laser source to emit the photodynamic laser energy for activating the photodynamic therapy agent after the liquid therapeutic agent has been administered to the body tissue region.

11. The laser pulse transmission assembly further comprises a microbiopsy suction conduit that communicates with the lumen of the cannula, The system further comprises a microbiopsy suction pump configured to cause a pressure drop in the microbiopsy suction conduit, The system according to any one of claims 1 to 3, wherein the control circuit is operably coupled to the microbiopsy aspiration pump, and the control circuit is further configured to control the microbiopsy aspiration pump so that the distal end of the cannula is inserted into the in vivo tissue region and the tissue in the in vivo tissue region is locally destroyed and liquefied, and then aspirates the liquefied tissue sample from the lumen of the cannula.

12. The laser pulse transmission assembly further comprises a suction conduit that communicates with the distal region of the cannula, The system further comprises a suction pump configured to cause a decrease in pressure within the suction conduit, The control circuit is operably coupled to the suction pump, The system according to any one of claims 1 to 3, wherein the control circuit is further configured to control the suction pump to aspirate the liquefied tissue in the suction conduit during local tissue destruction and liquefaction.

13. The navigation system comprises an ultrasonic imaging system, the ultrasonic imaging system configured to display on a user interface the position of the distal end of the optical fiber, which is determined based on the detection of a photoacoustic signal generated at the distal end during the transmission of an infrared laser pulse having laser pulse characteristics, according to any one of claims 1 to 3.

14. The system according to any one of claims 1 to 3, wherein the distal region of the cannula is tapered such that the outer diameter of the cannula decreases distally toward the distal end of the cannula.

15. The system according to any one of claims 1 to 3, wherein the diameter of the cannula exceeds the diameter of the optical fiber by less than 10% at the distal end of the cannula.

16. The system according to any one of claims 1 to 3, wherein the distal end of the cannula is provided with a slope.

17. The system according to any one of claims 1 to 3, wherein the distal tip of the optical fiber is provided with a slope so that the infrared laser pulse is emitted at an oblique angle with respect to the longitudinal axis of the optical fiber.

18. The system according to claim 17, wherein the inclination angle of the optical fiber is within 10% of the inclination angle of the distal end of the cannula.

19. The system according to claim 17, wherein the optical fiber is rotatable with respect to the body tissue region, and the control circuit is further configured to control the pulsed infrared laser source during rotation of the optical fiber after the distal tip of the optical fiber has been inserted into the body tissue region, thereby emitting infrared laser pulses having the laser pulse characteristics, thereby facilitating localized tissue destruction and liquefaction over an expanded volume within the body tissue region.

20. The system according to any one of claims 1 to 3, further comprising steering means for steering one or both of the cannula and the optical fiber.

21. The system according to any one of claims 1 to 3, wherein the laser pulse transmission assembly comprises one or more additional optical fibers, the optical fibers and the one or more additional optical fibers form an optical fiber bundle, the optical fiber bundle is optically coupled to the pulsed infrared laser source, and the infrared laser pulse is transmitted through the optical fiber bundle to the distal end of the optical fiber bundle.

22. The system according to claim 21, wherein at least two optical fibers of the optical fiber bundle have oblique distal tips configured to guide the infrared laser pulses in different directions.

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