Methods and apparatus for high speed and high aspect ratio laser subtractive material processing

Abstract

Exemplary embodiments of the disclosed apparatus and methods provide subtractive material processing, including efficient and precise ablation of tissue. One embodiment includes a first laser configured to direct a first pulse of energy at a first wavelength to a region of tissue, a second laser configured to direct a second pulse of energy at a second wavelength to the region of tissue, and a control system configured to control operation of the first laser and the second laser. In one embodiment, the control system is configured to control the duration of the first pulse of energy such that a vapor bubble forms in the region of tissue after the first pulse of energy is directed to the region of tissue.

Description

Background Art

[0001] (Cross - Reference to Related Applications) This application claims priority to U.S. Provisional Patent Application No. 62 / 847,577, filed May 14, 2019, the content of which is incorporated herein by reference.

[0002] (Background of the Invention) High - energy light sources (e.g., including lasers) are commonly used in devices and methods for tissue ablation in medical procedures. Such systems often do not provide an acceptable level of tissue removal rate, cutting accuracy, and minimization of non - specific collateral damage.

[0003] In typical existing systems, femtosecond and picosecond pulse - duration lasers are considered and emphasis is placed on high accuracy in tissue removal. However, the tissue removal rate in such systems can be unacceptably low. If a higher tissue removal rate is desired, the accuracy of removal and non - specific collateral damage can be sacrificed.

[0004] Conversely, in systems that place emphasis on a higher tissue removal rate, the accuracy and precision of tissue removal can be unsatisfactory. The increased energy associated with such systems can reduce the user's ability to precisely control the application and can lead to damage to surrounding tissue.

[0005] Thus, systems and methods are desired that overcome these and other limitations associated with existing systems and methods.

Summary of the Invention

Means for Solving the Problems

[0006] Exemplary embodiments of the present disclosure include systems and methods for rapid and precise ablation of tissue.

[0007] Lasers have been applied for many years for subtractive material processing. The laser subtractive process starts with spatially / temporally shaping the beam and directing the beam onto the material intended for subtractive processing from the environment. At a certain depth within the material after the incident laser radiation has passed through the environment-material interface, the laser radiation induces a phase change in the material (from solid to gas, from solid to plasma, from solid / liquid to gas, or from solid / liquid to plasma) and has a pulse fluence rate and / or pulse fluence energy sufficient to form bubbles. The bubbles contain hot gas or plasma or a combination (gas and plasma) and can generate a transient pressure greater than that of the surrounding material and / or within the environment that can lead to shock wave generation and bubble expansion.

[0008] In the process of developing a laser system for tissue surgery, the inventors constructed a thulium (Tm) laser system for high-speed tissue cutting. During development, the inventors noticed the limitations of using the Tm laser to cut tissue. The inventors applied Tm laser radiation to ex vivo and in vivo tissue and used optical coherence tomography (OCT) to observe the bubble formation and expansion process. The inventors observed that there was no consistency in the tissue removal rate efficiency and that it did not always provide clean and uniform cuts in the tissue. The Tm laser was originally selected to meet the conflicting requirements of high-speed and precise ablation. OCT images of the light-tissue interaction revealed that rapidly expanding vapor bubbles are formed when pulsed Tm laser light is incident on the tissue. It should be understood that the OCT images incorporated into the disclosed system are optional and that other embodiments of the present disclosure may not utilize OCT images.

[0009] The reason for the inconsistent Tm laser cutting efficiency is thought to be due to the way the rapidly expanding vapor bubble evolves over time. If the vapor bubble can provide sufficient shear force on the shallowest layer of the tissue, the bubble will tear the tissue surface and clean laser cutting will be achieved. If the expanding / collapsing bubble cannot provide sufficient shear force to tear the tissue, tissue cutting will not be achieved. The inconsistent operation of Tm-only laser ablation makes practical applications problematic.

[0010] Exemplary embodiments of the present disclosure address this drawback by providing additional pulses at laser wavelengths strongly absorbed by the tissue (e.g., Er:YAG at 2.94 microns or CO2 at 10.6 microns). The additional pulses at the strongly absorbed laser wavelengths are absorbed in the shallowest layer of the tissue and effectively provide additional shear force so that the expanding / collapsing vapor bubble can tear the tissue and clean ablation can be achieved. The inventors combined Tm (1.94 μm) and Er:YAG (2.94 μm) radiation. The device demonstrated high-speed and precise tissue ablation that was consistent and repeatable.

[0011] The application of two laser wavelengths achieved repeatable and consistent laser cutting of the tissue. By applying appropriate laser dosimetry for the two wavelengths, reliable and repeatable cutting can be achieved.

[0012] Exemplary embodiments thus provide an approach that enables high-speed and precise tissue cutting using currently available laser systems. Exemplary embodiments may increase costs compared to some existing single-laser systems, but such costs are thought to be outweighed by the increased efficiency of tissue removal rate while maintaining the desired accuracy.

[0013] Exemplary embodiments provide an approach that enables simultaneous (or near-simultaneous) high-speed and precise tissue cutting using a relatively standard laser system. For example, while very precise tissue cutting can be achieved using a femtosecond laser, the tissue removal rate is extremely slow. The advantages of using higher energy lasers (e.g., including a thulium (Tm) laser) for high-speed tissue removal have also not been realized. Laboratory experiments suggest that the problems associated with Tm-only laser ablation can result in inconsistent cutting and a thermal runaway effect that can cause substantial tissue damage. Previous attempts in Tm-only systems have not been successful due to these adverse effects. The exemplary embodiments of the present disclosure can address the problems encountered by Tm-only laser systems by also applying a second laser pulse energy that is strongly absorbed. In one particular embodiment, the second laser had a wavelength of 2.94 μm emitted from an Er:YAG laser.

[0014] An embodiment includes a method for subtractive material processing, the method including a defect induction step and a bubble generation step. In an exemplary embodiment, the defect induction step directs radiation onto the material from the environment to create a spatially constrained region with a reduced mechanical modulus within the material between the bubble generation site and the interface between the environment and the material, and the bubble generation step directs pulsed radiation onto the material from the environment to create subsurface bubbles below the environment-material interface. In a particular embodiment, material fracture due to bubble expansion occurs and is enhanced by a material region with a reduced mechanical modulus created by the defect induction step, resulting in material ejection.

[0015] In some embodiments, the material is cooled before, during, and after the bubble generation step. In a specific embodiment, the cooling is convective cooling. In one embodiment, the cooling is evaporative cooling. In one embodiment, the material is biological tissue. In a particular embodiment, the biological tissue includes structural inhomogeneities. In some embodiments, the structural inhomogeneity is an epithelial tissue layer. In a specific embodiment, the bubble generation step generates plasma. In one embodiment, the radiation emitted by an ultra-fast laser generates bubbles in the material. In a particular embodiment, the region of reduced mechanical modulus is shaped conically along the cone axis with a minimum modulus reduction. In some embodiments, the radiation for the defect induction step is obtained from the radiation source for the bubble generation step. In a specific embodiment, the radiation for the defect induction step is obtained from the pump radiation for the radiation source for the bubble generation step. In one embodiment, the radiation for the defect induction step is obtained from the radiation source for the bubble generation step through a non-linear conversion process.

[0016] In a particular embodiment, the defect induction step utilizes radiation in the range of 0.8 - 2.3 μm. In one embodiment, the bubble induction step utilizes radiation in the range of 0.4 - 2.3 μm. In a particular embodiment, the defect induction step utilizes a ytterbium (Yt) fiber laser. In some embodiments, the defect induction step utilizes an erbium (Er): glass laser. In a specific embodiment, the bubble generation step utilizes a thulium (Tm) laser. In one embodiment, the bubble generation step utilizes a holmium (Ho):YAG laser.

[0017] Certain embodiments include a method of ablating tissue, the method comprising directing a pulse of first energy at a first wavelength toward a region of tissue, such that a vapor bubble is formed within the region of tissue after the pulse of first energy is directed toward the region of tissue, and directing a pulse of second energy at a second wavelength toward the region of tissue, the pulse of second energy being directed toward the region of tissue after a bubble has been formed in the tissue, the pulse of second energy disrupting the mechanical integrity of the tissue surrounding the vapor bubble.

[0018] In some embodiments, the first wavelength is emitted by a thulium laser. In a specific embodiment, the second wavelength is emitted by an erbium laser. In one embodiment, the second wavelength is about 2.94 μm. In a particular embodiment, the first wavelength is emitted by a holmium laser. In some embodiments, the second wavelength is emitted by a carbon dioxide laser. Specific embodiments further include visually identifying the bubble via optical coherence tomography. In one embodiment, directing the pulse of first energy and the pulse of second energy toward the region of tissue includes directing the pulse of first energy and the pulse of second energy through a photonic crystal fiber. In a particular embodiment, directing the pulse of first energy and the pulse of second energy toward the region of tissue includes directing the pulse of first energy and the pulse of second energy through a germanium dioxide fiber.

[0019] One embodiment includes an apparatus comprising a first laser configured to direct a pulse of first energy at a first wavelength toward a region of tissue, a second laser configured to direct a pulse of second energy at a second wavelength toward the region of tissue, and a control system configured to control the operation of the first laser and the second laser. In certain embodiments, the control system is configured to control the duration of the pulse of first energy such that a vapor bubble is formed within the region of tissue after the pulse of first energy is directed toward the region of tissue, the control system is configured to control the operation of the first laser and the second laser such that a delay period exists between the pulse of first energy and the pulse of second energy, and the control system is configured to control the duration of the pulse of second energy such that the pulse of second energy disrupts the mechanical integrity of the vapor bubble.

[0020] In some embodiments, the first wavelength is emitted by a thulium laser. In a specific embodiment, the second wavelength is emitted by an erbium laser. In one embodiment, the second wavelength is about 2.94 μm. In certain embodiments, the first wavelength is emitted by a holmium laser. In some embodiments, the second wavelength is emitted by a carbon dioxide laser. Specific embodiments further include a conduit configured to direct the pulse of first energy and the pulse of second energy toward the region of tissue. In one embodiment, the conduit comprises a photonic crystal fiber. In certain embodiments, the conduit comprises a germanium dioxide fiber.

[0021] One embodiment includes a method of ablating tissue, the method comprising directing energy from an ytterbium laser to provide precoagulation of blood vessels within a region of tissue to be excised, directing energy from the ytterbium laser to raise the temperature of a region of tissue to be excised prior to excising the tissue, directing energy from a thulium laser to excise tissue from a region of tissue to be excised, and directing energy from the thulium laser to provide postcoagulation. Certain embodiments further comprise a delay period between directing energy from the ytterbium laser to provide precoagulation of blood vessels within a region of tissue to be excised and directing energy from the ytterbium laser to raise the temperature of a region of tissue to be excised.

[0022] As used below, the term "coupled" is defined as "connected", although not necessarily directly and not necessarily mechanically.

[0023] The use of the words "a" or "an" when used in conjunction with the term "comprising" in the claims and / or the specification may mean "one", but may also be consistent with the meaning of "one or more" or "at least one". The term "about" generally means ±5% of the stated value. The use of the term "or" in the claims is used to mean "and / or" unless explicitly indicated to refer to alternatives only or unless the alternatives are mutually exclusive, but the present disclosure supports definitions that refer to alternatives only and "and / or".

[0024] The terms "comprise" (and any form of comprise such as "comprises" and "comprising"), "have" (and any form of have such as "has" and "having"), "include" (and any form of include such as "includes" and "including"), and "contain" (and any form of contain such as "contains" and "containing") are conjunctive verbs without limitation. As a result, a method or device that "comprises", "has", "includes", or "contains" one or more steps or elements holds those one or more steps or elements, but is not limited to holding only those one or more elements. Similarly, an element of a method step or device that "comprises", "has", "includes", or "contains" one or more features holds those one or more features, but is not limited to holding only those one or more features. Further, a device or structure configured in a certain way is at least so configured, but may also be configured in ways not enumerated.

[0025] As used herein, the terms "cut" (and related terms such as "cutting") and "break mechanical integrity" (and related phrases such as "breaking mechanical integrity") are used to refer to processes that break molecular bonds in tissue.

[0026] As used herein, the term "light source" is understood to include any source of electromagnetic radiation, including, for example, a laser. It should also be understood that "a first light source" and "a second light source" can result from a single laser. For example, a laser configured to operate under a first set of parameters (e.g., wavelength, amplitude, continuous wave, or continuous pulse mode) can be regarded as "a first light source", while the same laser configured to operate under a second set of parameters can be regarded as "a second light source".

[0027] Other objects, features, and advantages of the present invention will become apparent from the following description of the embodiments for carrying out the invention. However, since various changes and modifications within the spirit and scope of the present invention will be apparent to those skilled in the art from the description of the embodiments for carrying out the invention, it should be understood that the description of the embodiments and specific examples are given by way of illustration only while showing specific embodiments of the present invention. The present invention provides, for example, the following. (Item 1) A method for subtractive material processing, the method comprising: a defect induction step; and a bubble generation step wherein the defect induction step directs radiation from the environment onto the material to create a spatially confined region with a reduced mechanical modulus within the material between a bubble generation site and an interface between the environment and the material; the bubble generation step directs pulsed radiation from the environment onto the material to create subsurface bubbles below the environment-material interface; material breakage due to bubble expansion occurs, and the material breakage is enhanced by the material region with the reduced mechanical modulus generated by the defect induction step, resulting in material ejection. (Item 2) The method according to Item 1, wherein the material is cooled before, during, and after the bubble generation step. (Item 3) The method according to Item 2, wherein the cooling is convective cooling. (Item 4) The method according to Item 2, wherein the cooling is evaporative cooling. (Item 5) ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ The defect induction step is the method according to item 5, which utilizes a ytterbium (Yt) fiber laser. (Item 17) The defect induction step is the method according to item 5, which utilizes an erbium (Er): glass laser. (Item 18) The bubble generation step is the method according to item 5, which utilizes a thulium (Tm) laser. (Item 19) The bubble generation step is the method according to item 5, which utilizes a holmium (Ho): YAG laser. (Item 20) A method for ablating tissue, the method comprising: directing a pulse of first energy at a first wavelength towards a region of the tissue, such that a vapor bubble is formed within the region of the tissue after the pulse of first energy is directed towards the region of the tissue; and directing a pulse of second energy at a second wavelength towards the region of the tissue; wherein the pulse of second energy is directed towards the region of the tissue after the bubble in the tissue is formed, and the pulse of second energy destroys the mechanical integrity of the tissue surrounding the vapor bubble. (Item 21) The first wavelength is emitted by a thulium laser, the method according to item 20. (Item 22) The second wavelength is emitted by an erbium laser, the method according to item 20. (Item 23) The second wavelength is about 2.94 μm, the method according to item 22. (Item 24) The first wavelength is emitted by a holmium laser, the method according to item 20. (Item 25) The second wavelength is emitted by a carbon dioxide laser, the method according to item 20. (Item 26) The method according to item 20, further comprising visually identifying the bubble via optical coherence tomography. (Item 27) Directing the pulse of first energy and the pulse of second energy towards the region of the tissue includes directing the pulse of first energy and the pulse of second energy through a photonic crystal fiber, the method according to item 20. (Item 28) Directing the pulse of first energy and the pulse of second energy towards the region of the tissue includes directing the pulse of first energy and the pulse of second energy through a germanium dioxide fiber, the method according to item 20. (Item 29) An apparatus, the apparatus comprising: A first laser configured to direct a pulse of first energy at a first wavelength toward a region of tissue, a second laser configured to direct a pulse of second energy at a second wavelength toward the region of tissue, and a control system configured to control the operation of the first laser and the second laser comprising, wherein the control system is configured to control the duration of the pulse of first energy such that a vapor bubble is formed within the region of tissue after the pulse of first energy is directed toward the region of tissue, wherein the control system is configured to control the operation of the first laser and the second laser such that a delay period exists between the pulse of first energy and the pulse of second energy, wherein the control system is configured to control the duration of the pulse of second energy such that the pulse of second energy disrupts the mechanical integrity of the vapor bubble, an apparatus. (Item 30) The apparatus according to item 29, wherein the first wavelength is emitted by a thulium laser. (Item 31) The apparatus according to item 29, wherein the second wavelength is emitted by an erbium laser. (Item 32) The apparatus according to item 31, wherein the second wavelength is about 2.94 μm. (Item 33) The apparatus according to item 29, wherein the first wavelength is emitted by a holmium laser. (Item 34) The apparatus according to item 29, wherein the second wavelength is emitted by a carbon dioxide laser. (Item 35) The apparatus according to item 29, further comprising a conduit configured to direct the pulse of first energy and the pulse of second energy toward the region of tissue. (Item 36) The apparatus according to item 35, wherein the conduit comprises a photonic crystal fiber. (Item 37) The apparatus according to item 35, wherein the conduit comprises a germanium dioxide fiber. (Item 38) A method of ablating tissue, the method comprising: directing energy from an ytterbium laser to provide precoagulation of blood vessels within a region of tissue to be excised; directing energy from the ytterbium laser to increase the temperature of the region of tissue to be excised prior to excising the tissue; directing energy from a thulium laser to excise tissue from the region of tissue to be excised Directing energy from the thulium laser to provide post-excision coagulation A method comprising. (Item 39) The method according to item 38, further comprising a delay period between directing energy from the ytterbium laser to provide pre-coagulation of blood vessels within the area of tissue to be excised and directing energy from the ytterbium laser to increase the temperature of the area of tissue to be excised.

Brief Description of the Drawings

[0028] The patent or application file includes at least one drawing executed in color. A copy of this patent or patent application publication with color drawings will be provided by the Patent Office upon request and payment of the required fees.

[0029] The following drawings are included to form a part of this specification and further demonstrate certain aspects of the disclosure. The invention can be further understood by reference to one of these drawings in combination with the forms for carrying out the invention presented herein.

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[0061] Exemplary embodiments of the present disclosure include apparatuses and methods that provide efficient and precise ablation of tissue. It should be understood that the embodiments described herein are merely exemplary and that other embodiments are also included within the scope of the present invention.

[0062] Referring now to FIG. 1, an exemplary embodiment of system 50 includes a first light source 100, a second light source 200, and a control system 300 configured to control the operation of the first and second light sources 200 and 300. In the illustrated embodiment, the first light source 100 can be configured as a laser that directs a pulse 110 of first energy at a first wavelength toward a region 500 of tissue. Additionally, the second light source 200 can be configured, in this embodiment, as a laser that directs a pulse 210 of second energy at a second wavelength toward the region 500 of tissue. In certain embodiments, system 50 can include a conduit 400 configured to transmit the first and second pulses 110 and 210 of energy from the first and second light sources 100 and 200 to the region 500 of tissue. The energy 410 (e.g., the first pulse 110 of energy and the second pulse 210 of energy) from the light sources 100 and 200 can then be directed toward and incident on the region 500 of tissue.

[0063] In one embodiment, the conduit 400 can be configured as a catheter with a distal end 405 that can be placed in proximity to the tissue region 500. In some embodiments, the conduit 400 can comprise a photonic crystal fiber, and in a specific embodiment, the conduit 400 can comprise a germanium dioxide fiber. In certain embodiments, one or more fibers can be housed and sealed within an extruded article, whereby the risk of tissue contact can be appropriately reduced.

[0064] During operation of the embodiment shown in FIG. 1, the control system 300 is configured to control the duration of the first energy pulse 110 from the light source 100 and the second energy pulse 210 from the light source 200. Additionally, the control system 300 is configured to control the operation of the first light source 100 and the second light source 200 such that a delay period exists between the first energy pulse 100 and the second energy pulse 210.

[0065] In a particular embodiment, the control system 300 is configured to control the duration of the first energy pulse 110 such that after the first energy pulse 110 is directed towards the tissue region 500, a vapor bubble 500 is formed in the tissue region 500. The control system 300 is configured to control the duration of the second energy pulse 210 such that the second energy pulse 210 reduces or destroys the mechanical integrity of the tissue overlapping the vapor bubble 500.

[0066] The ability to form vapor bubbles using a first energy pulse at one wavelength and reduce or destroy the mechanical integrity of tissue overlapping the vapor bubbles using a second energy pulse at a second wavelength provides significant advantages over existing systems. For example, tissue ablation can be more precisely controlled and performed more efficiently than with single-wavelength systems. In particular, single-wavelength systems utilizing femtosecond lasers can provide precise tissue removal but at a very slow rate. This can lead to extensive times required for procedures that require significant amounts of tissue ablation. Conversely, single-wavelength systems utilizing thulium lasers can provide faster tissue removal but without precise control. This can result in damage to healthy tissue not intended for removal or ablation. Exemplary embodiments of the present disclosure provide the ability to precisely and efficiently ablate tissue by utilizing a first wavelength for forming vapor bubbles in the tissue and a second wavelength for reducing and / or destroying the mechanical integrity of tissue overlapping the vapor bubbles (e.g., by ablating a layer of tissue covering the vapor bubbles).

[0067] Referring now to FIG. 2, flowchart 600 includes an overview of steps in a method of using an apparatus according to an exemplary embodiment that includes, for example, apparatus 50 shown in FIG. 1. Flowchart 600 includes a first step 610 of directing a pulse of first energy at a first wavelength toward a region of tissue, and thereafter, following the directing of the pulse of first energy toward the region of tissue, a second step 620 of forming a vapor bubble in the region of tissue. Next, flowchart 600 includes a step 630 of directing a pulse of second energy at a second wavelength toward the region of tissue after the bubble has been formed. Finally, step 640 includes reducing and / or destroying the mechanical integrity of the vapor bubble.

[0068] It should be understood that flowchart 600 provides only a general overview of steps in an exemplary method. For example, additional steps, including steps for visually identifying the bubble via optical coherence tomography, may be included in certain embodiments.

[0069] Next, referring to FIG. 3, an image of the bubble 500 resulting from a pulse of energy from the first light source is shown. FIG. 4 illustrates the result after a second pulse of energy from the second light source is directed at the same area of tissue shown in FIG. 3. As shown in FIG. 4, the ablated area 550 occurs after the mechanical integrity of the tissue overlapping the bubble 500 is reduced or destroyed.

[0070] FIGS. 5 and 6 provide front images of the tissue in which the ablated area is shown as a darker area in the tissue. As shown in the figures, the ablated area can be clearly defined and precisely controlled.

[0071] FIGS. 7 and 8 provide cross-sectional views of the tissue before and after tissue ablation according to the present disclosure. Again, the ablated area shown in the cross-sectional view is clearly defined.

[0072] FIGS. 9 and 10 provide front views of the ablated holes formed in porcine skin using the apparatus and method as disclosed herein. As shown in the figures, the holes have a diameter of less than 30 μm and a depth of about 200 - २२५ μm.

[0073] Further explanation and illustration of the operating principle can also be found in the following discussion of examples and results. (Examples)

[0074] The following examples are included to demonstrate preferred embodiments of the present disclosure. The techniques disclosed in the following examples represent techniques that have been found by the inventors to function well in the practice of the present disclosure, and thus, it should be understood by those skilled in the art that they may constitute a preferred mode for its practice. However, those skilled in the art will understand that, based on the present disclosure, many changes can be made to the disclosed specific embodiments and still obtain similar or analogous results without departing from the spirit and scope of the present disclosure.

[0075] Referring now to FIG. 11, an OCT-guided laser surgical device is shown with co-aligned ytterbium and thulium (Yt / Tm) beams. In this embodiment, it should be understood that a Mach-Zehnder fiber interferometer uses a circulator (CR) and balanced detection (BD) and is dispersion compensated (CM). The Tm / Yt and OCT beams are fiber-delivered via a collimator (RC) and combined with a dichroic mirror (DM).

[0076] Experiments were performed using the apparatus shown in FIG. 11 to demonstrate the effectiveness of the methods disclosed herein. In particular, since absorption in blood is specifically higher than that in surrounding native tissue, three brain surgeries were performed on control mice using a ytterbium fiber laser (1070 nm) for blood-specific coagulation. In addition, a thulium nanosecond fiber laser was used to remove brain tissue due to its higher tissue absorption.

[0077] Generally, a combination of Yt / Tm lasers was utilized to provide pre-coagulation of blood vessels and pre-heating of tissue prior to resection / ablation, followed by post-resection / ablation coagulation. An overview of the aspects utilized in the method is provided in FIG. 12. Method 105 comprises a first aspect 115 in which energy is directed from a Yt laser to provide pre-coagulation of blood vessels within the area to be resected to avoid bleeding after the tissue has been removed. This is followed by aspect 125 which includes pre-heating of the area by the Yt laser (e.g., by directing energy from the ytterbium laser prior to resection of the tissue to raise the temperature of the area of tissue to be resected), which pre-heating is performed to assist Tm nanosecond tissue resection. In the embodiment shown in FIG. 12, the procedure then provides tissue resection by the Tm laser in aspect 135. In some embodiments, the Yt laser may continue to emit during Tm resection and minimize or eliminate bleeding after resection. In addition, the procedure utilizes the Tm laser in aspect 145 of method 105 to provide post-resection coagulation to reduce or prevent bleeding after local tissue removal.

[0078] In a specific embodiment, the initial coagulation step using a Yt fiber laser can be optimized to coagulate the entire distribution of blood vessel sizes. For example, the dosimetry can be adjusted to coagulate all blood vessel sizes (e.g., veins and arterioles) within the target area. The preheating aspect of the procedure (as an adjustment step for modifying the shear modulus and viscosity of the tissue) using the Yt laser is an important aspect of the exemplary method. In this aspect, the Yt laser can be used to transiently heat the target tissue up to the point where protein denaturation (which will depend on the Arrhenius rate process for the tissue surrounding the blood vessels) is about to occur outside the vascular system. If the proteins surrounding the blood vessels denature during the preheating step, the efficiency of Tm resection will decrease. Thus, the Tm laser performs resection more efficiently using the preheating aspect disclosed herein.

[0079] FIG. 13 provides a schematic diagram of Yt and Tm laser amplitudes versus time at various aspects of the procedure according to the present disclosure. In particular, FIG. 13 illustrates the Yt and Tm laser applications during the precoagulation period, delay period, ablation period, and after resection / ablation as shown in the figure.

[0080] FIG. 14 displays the results of a first example of a mouse brain surgery using Yt / Tm laser application as described herein. The left image shows an angiogram of the blood vessels before surgery. The upper central image shows an angiogram of the blood vessels after surgery, while the bottom central image shows an overlay of the images. The central (red) portion shows the occluded (e.g., resected / ablated) vascular system. The right image is a cross-section of the tissue after surgery.

[0081] FIG. 15 displays the results of a second example of a mouse brain surgery using Yt / Tm laser application as described herein. The left image is an angiogram of the blood vessels before surgery, while the right image is an angiogram of the blood vessels after surgery.

[0082] Figure 16 shows the results of a third example of mouse brain surgery using Yt / Tm laser application as described herein. The left image is an angiogram of the blood vessels before surgery, while the right image is an angiogram of the blood vessels after surgery. The image in the lower central part of the figure is a cross-section of the tissue after surgery.

[0083] Referring now to Figure 17, when there is laser-induced bubble generation and an increase in pressure due to gas and / or plasma generation, high-speed bubble expansion occurs. In an elastic material that can support a certain amount of shear stress (i.e., not a pure liquid), the free energy stored in the high-temperature gas and / or plasma contained within the bubble is converted into stored elastic energy in the surrounding material as the bubble expands. During the high-speed expansion and / or collapse of a laser-generated bubble, existing material inhomogeneities can break and grow and expand into microcracks at candidate sites. Many types of material inhomogeneities are recognized in various materials (e.g., skin, Panel A, Figure 17). Exemplary material inhomogeneities can include, but are not limited to, for example, structural interfaces, atomic or molecular interfaces, phase interfaces such as liquid / gas, protein / liquid, protein / gas, density gradients, entropy defects or gradients. If the laser-induced stress is of sufficient magnitude, microcrack growth can be initiated at material inhomogeneities, chain together, and result in more extensive fragmentation. The chain of microcracks leading to fragmentation will generally initiate along material inhomogeneity boundaries and propagate through the material. If the fragmentation propagates upward toward the environment / material interface (i.e., air / material or liquid / material), separates or divides the environment / material interface, and the material overlapping the bubble has sufficient momentum, the material near the fragmented region can be "blown out", resulting in "cutting" of the material, which is the design objective of subtractive laser material processing (Panel B, Figures 17-18). Thus, the process of laser subtractive processing involves causing laser radiation to impinge from the environment onto the material, achieving sufficient fluence and / or fluence rate within the material to generate bubbles that rapidly expand within the material, and causing microcracks to grow at one or more material inhomogeneities due to the laser-induced stress. Bubble-induced microcrack growth has a component of propagation perpendicular to the environment / material interface and can develop and chain into material fragmentation that ultimately results in a blowout event surrounding the bubble with a portion of the material ejected into the environment (Figure 18). In some cases, microcrack growth is insufficient to cause fragmentation, or the fragmentation does not propagate to the material / environment interface and a material blowout event does not occur (Figure 19).In other materials, there are extensive existing material inhomogeneities, as is often the case with biological tissues. When bubble generation is in or below the structural layer, fracture propagation can proceed along the lower structural boundary and not propagate to the environmental-material interface, thereby preventing the occurrence of blowout events (Panel B, Figure 19). In cases where blowout events do not occur, laser subtractive processing fails, and the properties of the target material can be adversely affected.

[0084] For more efficient laser subtractive processing and higher material removal rates, more extensive bubble formation deeper within the material is required such that a larger amount of material overlapping the bubbles results in more material being removed per incident laser pulse. However, when bubbles can be generated at deeper positions within the material, microcrack growth resulting from bubble expansion becomes more unpredictable. For bubble formation at deeper positions, bubble expansion must be sufficient to generate microcracks that propagate to some extent along the interface normal to the environmental-material interface and ultimately fractures, resulting in a material blowout event. For deeper bubble formation resulting in a material blowout event, the pulse fluence or pulse fluence rate required to generate expanding bubbles must be considered. For example, if the pulse fluence or pulse fluence rate is too low and expanding bubbles can be generated at deeper positions within the material, microcrack growth may be insufficient to generate fractures that propagate to the environmental-material interface, and blowout events do not occur. Additionally, although increased pulse energy can be applied to generate more active bubbles, existing material inhomogeneities can redirect microcracks and fractures parallel to or away from the environmental-material interface such that blowout events do not occur.

[0085] In cases where cracking does not propagate upward and does not split or break the material / environment interface, at least three events can impair the laser subtractive process. First, the material does not eject, and the intended material subtraction event does not occur. Second, the thermal energy generated from the subsurface laser-material interaction becomes trapped inside the material, which can result in local non-specific melting, molecular unfolding, bond breaking, and chemical modification. Third, the resulting thermal damage, melting, and molecular changes modify the functional, optical, mechanical, and chemical properties of the remaining material, not only preventing material subtraction by the application of subsequent laser pulses but also potentially affecting the material for its intended use.

[0086] In biological materials, infrared laser radiation (0.8 μm to 2.6 μm) can be used to generate bubbles within the tissue at a depth greater than 80 μm below the environment-material interface, but the microcrack growth and fracture propagation to the environment-material interface can be unpredictable or insufficient to generate an ejection event for subtractive processing. Some laser sources that target specific chromophores, such as water that targets an Er:YAG (2.940 μm) or CO2 (10.6 μm) laser, enable superficial bubble generation and precise tissue removal but cannot achieve high aspect ratio cutting and do not provide a high material removal rate. Conversely, laser systems that provide deeper penetration of radiation in the target material enable bubble generation at deeper positions, but microcrack and fracture generation are less predictable and have a higher likelihood of not resulting in a material ejection event. When an ejection event does not occur, the predictability of the action of subsequent laser pulses is sacrificed, and material functionality can be lost. For example, non-specific thermal damage to nerve tissue can result in patient physical impairment, and non-specific thermal injury is a particular problem in some laser medical surgical procedures.

[0087] Embodiments of the present invention enable a consistent high material removal rate with a high aspect ratio by creating transient and spatially confined viscoelastic inhomogeneities in a material, such that when expanding bubbles are generated at relatively deep positions, microcrack growth and fracture propagation can reliably and repeatedly propagate to produce an ejection event. The transient viscoelastic inhomogeneities created in the material are designed such that microcrack and fracture generation due to bubble expansion propagate with a component along the perpendicular to the environment - material interface, reliably and consistently resulting in an ejection event with minimal residual non - specific damage to the remaining material. Accordingly, radiation sources, systems, and methods are described that overcome the existing limitations associated with laser subtractive systems and methods.

[0088] In the process of developing a laser material removal system for applications in biological tissues, the inventors constructed a thulium (Tm) laser system for high - speed tissue cutting. The goal of the development effort was to leverage the deeper penetration of Tm laser light in tissue (compared to CO2 or Er:YAG; Figure 17, panel A) to achieve a higher volumetric tissue removal rate and meet the conflicting requirements of fast and precise tissue removal for various laser surgical procedures. During development, the inventors used a short - pulse (100 nanosecond) Tm laser and observed severe limitations and unpredictability in cutting or removing tissue. To investigate the material removal process, the inventors applied the Tm laser to a number of ex vivo and in vivo tissues and used optical coherence tomography (OCT) images ([3,4]) to study the ablation process. The inventors observed that the interaction of Tm radiation with many materials and tissues, bubble generation, and material response were inconsistent and did not always provide an ejection event. OCT images recorded during Tm tissue irradiation showed inconsistent tissue removal and indicated that the Tm laser was unable to provide clean and uniform ablation of both ex vivo and in vivo tissues, including skin, muscle, brain, and fat. Furthermore, the inventors observed non - specific thermal damage in many tissues, regardless of the presence or absence of an ejection event.

[0089] In the OCT images of the ablation process, it was confirmed that when a pulsed Tm laser beam with sufficient fluence is incident on the target tissue, rapidly expanding vapor bubbles are formed. As described above, the laser material removal process involves shock wave propagation, bubble formation, expansion, and collapse that impart large shear stresses to the material [5]. The stresses associated with shock wave propagation, bubble expansion, and collapse interact with material inhomogeneities and, if large enough, result in microcrack growth and propagation of fragmentation. Observations in both ex vivo and in vivo tissues confirmed that Tm laser irradiation with sufficient fluence can generate gas-filled bubbles within the tissue, but subsequent bubble expansion and collapse generate unpredictable microcracks and fragmentation. In most cases, the fragmentation did not propagate to the tissue interface and did not result in ejection events and material ejection. In some tissues such as the skin, bubble-induced fragmentation propagated along the epithelial tissue boundary and did not reach the air-tissue interface and did not result in ejection events and material ejection. In these cases, extensive non-specific residual thermal damage was observed in the tissue.

[0090] At the present stage, it is important to note the observed differences in the interaction of pulsed Tm laser radiation with a gelatin phantom compared to various ex vivo and in vivo tissues. Experiments using a gelatin phantom highlight the influence that material inhomogeneities have in laser subtractive processes in actual tissues. Some of the differences between the gelatin phantom and tissue include that the gelatin phantom is a more homogeneous material with little inherent inhomogeneity, in contrast to most tissues that have multiple types of inhomogeneities. In many tissues, there are structural inhomogeneities that support function and can affect mechanical damage in response to bubble generation. In the gelatin phantom, the application of Tm pulsed radiation that did not consistently remove material in ex vivo and in vivo tissues consistently generated gas-filled bubbles that resulted in damage propagating to the air-gelatin interface and resulted in ejection events and material removal (Figs. 20-21).

[0091] Tm laser ablation experiments using gelatin phantoms demonstrate the importance of tissue inhomogeneity in laser subtractive processing of heterogeneous materials such as biological tissues. Laser-induced bubbles can be generated in both gelatin phantoms and tissues, but subsequent microcracking and fragmentation propagation can be very different. In homogeneous gelatin phantoms, microcracking and fragmentation propagation to the surface with material ejection were controlled and predictable. In contrast, in tissues, microcracking could be observed, but fragmentation generation and propagation were highly unpredictable and did not frequently result in material ejection events. Furthermore, in tissues, increasing the Tm pulse energy and / or fluence to generate more active bubbles did not produce the desired effect of consistent repeatable ejection.

[0092] For example, in tissues, even when the pulse duration and energy satisfy the entropy conditions for water [6] and the confinement results in little residual surface evaporation such that it is observable through OCT [6], the collapse of laser-generated vapor bubbles led to various scenarios. Two such scenarios are: 1) sufficient bubble-induced tensile and shear stresses to cause microcracking and tension and / or shear failure that propagates to the tissue surface resulting in material ejection (Figure 22, panels I, IIB), or 2) sufficient bubble-induced tensile and shear stresses to cause fragmentation formation with insufficient components along the interface normal such that material damage near the surface does not occur leaving significant residual damage in the form of high-temperature residues trapped inside the tissue (Figure 22, panel IIA). Unfortunately, scenario 1 was inconsistent and unpredictable and could not be repeatedly applied for tissue cutting.

[0093] A novel approach for assisting laser subtractive processing is described by creating transient viscoelastic inhomogeneities in a target material such that microcracks and fragmentation resulting from bubble expansion propagate to the environment-material interface in a more predictable manner, reliably and consistently resulting in ejection events. This innovative approach uses absorbed laser radiation (different from that used to generate bubbles) to reduce the viscoelastic modulus of the target material and then generates transient inhomogeneities that can provide some control over the direction of microcracking, fragmentation, and material ejection in response to bubble generation. This approach is particularly relevant when bubble generation is targeted at deeper locations within an inhomogeneous material. Because in those cases, the native material inhomogeneities can unfavorably define the direction of preferred microcracking and fragmentation. In some cases, the native material inhomogeneities can be unknown (even in a statistical sense), whereby microcracking and fragmentation propagation in response to bubble generation propagate in a random manner, making the laser subtractive processing inconsistent and unpredictable. In other cases, the existing native material inhomogeneities are well-known and can have a highly predictable orientation, however, microcracking and fragmentation along these existing boundaries can act contrary to the bubble-induced ejection event. In some biological tissues, for example, epithelial tissue boundaries represent primary material inhomogeneities and can have a natural orientation parallel to the environment / material interface. When laser-induced bubble generation occurs within these biological materials at a location directly below or near the epithelial layer, the resulting microcracking and fragmentation propagation has a higher likelihood of proceeding along the epithelial-tissue boundary. In these cases, laser-induced bubble generation can form fractures along the epithelial tissue boundary and no ejection event occurs.

[0094] Pulsed laser radiation can be utilized to generate spatially controlled transient viscoelastic inhomogeneities in a target material. In many materials, the viscoelastic modulus is temperature dependent and will assume a reduced magnitude with the temperature rise that can be induced by the absorption of pulsed laser radiation ([7,8]). By reducing the viscoelastic modulus of the material within a spatially confined region near the bubble generation site, transient inhomogeneities are generated within the material. In the material region where the temperature is raised and the viscoelastic modulus is reduced, the strain rate (Equation 1, where G is the shear modulus) generated by shock waves and expanding and collapsing bubbles is increased. In the material region with a reduced viscoelastic modulus, higher strain rates and spatial gradients of strain rates can more readily chain together via material fragmentation propagating along an interface perpendicular to the surface that results in material ejection and blowout events with components along the interface. Thus, pulsed laser radiation can be utilized to generate spatially controlled transient viscoelastic inhomogeneities in a target material that direct fracture propagation towards the surface and result in blowout events. This concept of spatiotemporally controlled reduction of the viscoelastic properties of a target material to increase strain rate, microcrack generation, and fracture propagation is applicable not only to various inhomogeneous materials such as biological tissues, but also to other material removal techniques such as polymer processing, material processing, and related industrial processes.

Number

[0095] Spatially controlled transient viscoelastic heterogeneities can be generated in a target material to control and propagate fragmentation in response to bubble generation, but physical constraints on the methodology are recognized for effective implementation. In polymer- or protein-based materials, a transient increase in temperature can reduce the viscoelastic modulus ([7,8]), but a long-term temperature increase over a longer duration can result in protein denaturation that increases the viscoelastic modulus. Thus, if the time-integrated temperature increase to reduce the viscoelastic modulus is excessive or too long, the reduced strain rate resulting from bubble expansion and collapse can limit microcrack formation. Therefore, the methodology we describe involves two steps, which are described as a defect-inducing step (Step A) and a bubble-forming step (Step B), respectively. The bubble-forming step (Step B) generates bubbles that rapidly expand at a subsurface location within the material. The temporal relationship between the defect-inducing step (Step A) and the bubble-generation step (Step B) is an important consideration and depends on the time-dependent optical, mechanical, chemical, and thermal properties of the target material. For the purposes of this discussion, the bubble-generation step (Step B) is considered to start at time t = 0 and is associated with the laser pulse duration τ B . The defect-inducing step (Step A) is assumed to start at time t A,1 and continue until time t A,2 , and these times are referenced to the start of the bubble-forming laser pulse. During the defect-inducing step (Δt A = t A,2 - t A,1 ), one or more depositions of laser radiation can be incident on the target material to control the size and spatial extent of the induced viscoelastic defects. Fine-tuning the temporal relationship between the defect-inducing step and the bubble-generation step enables optimal effectiveness of material removal.

[0096] In some applications, commercial constraints limit the choice of light sources to complete steps A and B. In these cases, the radiation to complete step A can be obtained from the laser source used to complete step B. For example, the radiation for the defect induction step (step A) can be obtained from the pump light source for the laser used for bubble generation (step B). Modern laser sources frequently utilize very bright fiber lasers or laser diodes as pump sources so that radiation for defect induction can be obtained therefrom. For example, an approach for generating the radiation for the defect induction step (step B) can directly utilize the pump source for the bubble generation laser. Alternatively, the defect induction step can utilize a non-linear conversion process to shift either the pump light and / or any wavelength of the laser emission from the laser used for bubble generation (step B). For example, a Raman fiber laser can be utilized to generate laser radiation over a broad wavelength range within the infrared spectrum and represent a candidate approach to achieve a wavelength shift for the source for the defect induction step (step A).

[0097] Bubbles generated by a laser containing any of gas [9],

[10] , plasma

[11] ,

[12] , or a combination thereof (

[10] ) can be formed. The laser wavelength (λ B ) used in the bubble formation step can be selected by utilizing linear and / or non-linear absorption processes in the target material. For plasma bubble formation, the non-linear or multi-photon absorption characteristics of the material are considered. The bubble formation laser wavelength (λ B) The options are also determined by the availability of light sources. Readily available laser wavelengths that target the linear absorption process in materials containing water (e.g., tissues) are thulium / Ho:YAG (1.94 μm / 2.01 μm). Short-pulse (picosecond to femtosecond) lasers that utilize at least partially the non-linear absorption process to provide cavitation can be used. The practical usefulness of the non-linear absorption process for cavitation is that the material phase change resulting from light absorption is extremely spatially confined locally to the target region within the material. Laser dosimetry (spot size, pulse duration, incident fluence) for the cavitation step (step B) that utilizes the linear or non-linear absorption process in the target material is known in the art

[12] , and the cavitation is at a subsurface depth (z o ) in the material where sufficient fluence (J / cm 2 ) or fluence rate (W / cm 2 ) can be achieved. The laser dosimetry for step B should take into account the optical properties of the material, including scattering (μ s ), anisotropy (g), and absorption (μ a ). Cavitation in heterogeneous scattering tissues can be achieved at deeper locations by adopting various optical clearing approaches to reduce the scattering intensity of the material

[12] .

[0098] The purpose of the defect-inducing step (step A) is to generate controlled heterogeneities in the material such that, in response to the cavitation step (step B), increased microcracks and reliable fracture propagation to the material / environment interface occur. In one embodiment, the defect-inducing step (step A) generally uses the light absorption (μ o ) process within the target material region at a depth (z) between the site of cavitation (z a ) and the material / environment interface (z = 0) to transiently increase the material temperature (ΔT A ). In this embodiment, the laser wavelength (λ A) And the selection of the dose measurement (spot size, pulse duration, incident fluence) must consider the optical fluence (Φ) within the material region surrounding the site of bubble generation (step B), and the thermal properties of the material including the heat capacity (C) and mass density (ρ), in accordance with the following.

Number

[0099] The material temperature rise (ΔT A ) generated by the laser in step A must be sufficient to reduce the viscoelastic modulus of the material, increase the strain rate and microcrack formation, and ensure crack propagation to the material / environment interface. At the same time, the material temperature rise (ΔT A ) generated by the laser in step A must be short enough (with respect to the time of bubble generation and expansion) so that no large material phase change (e.g., thermal denaturation) occurs that could limit microcrack growth and crack propagation.

[0100] In biological tissues, a temperature rise (ΔT A ) that is too large over a duration (Δt A ) that is too long can result in protein denaturation and can harmfully modify the induced defects. The Arrhenius integral and associated damage parameter (Ω, equation 3) provide a measure of the level of protein denaturation that occurs during the defect induction step. Excessive protein denaturation (Ω of about 1) is associated with an increase in the shear elastic modulus and is another temporal consideration that constrains the options for the duration (Δt A ) of the defect induction step.

Number

[0101] In the field of laser-tissue thermal interactions, the Arrhenius activation energy per molecule (E a ) and the reaction rate (A o ) for tissue damage and the critical temperature depend on the tissue type [13, 14], the temperature rise (ΔT A) varies based on its magnitude, duration, and spatial distribution in the tissue. For example, in the skin, the critical temperature for damage typically ranges from 50 to 60 °C, while in muscle, it varies from 60 to 70 °C. Temporally, this critical temperature for damage rises by 5 °C with respect to the total decay reduction of the pulse duration. This is based on the ability to heat the tissue to a higher temperature before any tissue damage (as indicated by the Arrhenius damage integral value), suggesting the desirability of using short-pulse lasers to shorten the defect-induced duration (Δt A ). By utilizing short-pulse lasers, higher temperatures can be achieved in some materials with further reduction of the viscoelastic modulus and additional control resulting from crack propagation, by shortening the defect-induced duration (Δt A ). Since Arrhenius damage is associated with an increase in the shear elastic modulus, it is desirable to design an adjustment duration (Δt A ) that is short enough to reduce viscosity and bulk / shear elastic modulus and increase the strain rate and microcrack propagation while avoiding excessive molecular denaturation (about 1 of Ω).

[0102] Another temporal consideration is defect induction in the material during bubble expansion and collapse. In this case, t A,2 extends until the time of bubble expansion and / or collapse. Continuous strain rate impulses can be achieved by delivering short-duration laser pulses (e.g., nanoseconds) that enhance defect induction, are absorbed by the material surrounding the bubble, rapidly reduce the viscoelastic modulus, and amplify the non-linear growth of microcracks and crack propagation. Another temporal effect relates to continuous material ejection events at one lateral position. To achieve continuous material ejection events, the properties of the material remaining from the previous ejection event (e.g., temperature) should be considered for subsequent defect induction steps. Thus, the residual effect of the previous ejection event can transfer to subsequent defect induction steps and reduce the required temperature increase (ΔT A ) for subsequent defect induction events.

[0103] The defect induction step enhances each ejection event and aids in the removal of residual absorbed laser radiation, but additional thermal energy can be removed from the material during and after the ejection event by cooling. Nonspecific residual thermal changes in the target material undergoing subtractive processing can be mitigated using a cooling approach. Cooling can be initiated prior to the bubble generation step (step B), during bubble expansion and collapse, or after material ejection. For example, various cooling approaches including evaporation, convection, and conduction with a phase change are recognized in the art. An approach utilizing conduction must be configured such that the conductive media heat does not substantially interfere with either the ejection event or subsequent defect induction events (i.e., from the material undergoing subtractive laser processing). Passive or forced gas convection cooling provides the advantage of enhanced convective removal of the ejected material without interfering with either the ejection event or subsequent defect induction events. Evaporation with a phase change typically has a higher heat transfer coefficient compared to either a conductive or convective cooling approach, but the residence time of the phase change material can extend the application time of any required subsequent defect induction step.

[0104] Spatial patterning (grid pattern irradiation) is possible for steps A and B, enabling material removal at the grid points. A large number of spatial patterns can be envisioned where ablation is enabled by controlling the spatial distribution of the temperature rise in the defect induction step and the application of the bubble induction step. By spatially patterning the temperature rise in the defect induction step, microcrack propagation and fracture propagation can be spatially confined to selected regions within the target material. For example, utilizing an axicon for the defect induction step can be configured to generate a conical region with a constrained surface ([15, 16]) such that fracture propagation and material ejection are spatially controlled and limited to a conical region. An axicon configuration combined with bubble generation and multiphoton absorption and plasma generation using an ultrashort pulsed laser can provide material ejection with minimal thermal modification to a relatively large tissue volume. This configuration can be useful for tissue sampling or fine biopsy such that a diagnostic screening approach can be applied to characterize the tissue taken. Fine biopsy involving high-speed screening of tissue using optical (e.g., Raman) mass spectrometry or radio frequency approaches can assist in cancer surgery.

[0105] Consider the following in connection with the above factors in tissue ablation and exemplary embodiments on the same line with a controlled temporal reduction of the shear modulus tested in vitro and in vivo tissue for surgery.

[0106] The defect induction step (Step A) was tested using a ytterbium (Yt) fiber laser (1.0 μm) by applying a laser pulse aligned with the radiation for the bubble generation pulse and inducing a spatiotemporally controlled non-uniformity in the target material for subtractive laser processing. The bubble generation step (Step B) utilized a thulium fiber laser (1.94 μm wavelength) aligned with the radiation (1.07 μm) emitted by the Yt fiber laser for defect generation. At the environment-material interface, the light emitted from the Yt fiber laser irradiated a slightly wider lateral region than that from the bubble generation light source (in this example, the thulium fiber laser). The absorbed Yt laser light increased the temperature of the target material and reduced the viscoelastic modulus of the material so that bubble generation by the Tm laser would surely result in a material ejection event. This approach is illustrated in FIG. 22 where the transient defects generated by the laser (Yt) are shown as brown regions. The material (in this case, tissue) removal rate in this scheme has increased by several orders of magnitude from a relatively small 15 W value (Ahmadi et al., 2017; Katta et al., 2017) to 1 kW, a 66.7-fold increase, over the past few years, limited only by the average power of the bubble generation light source (in this case, the thulium fiber laser). Different temperature rises (ΔT A ) were induced in the defect induction step in various tissue types (Table 1). Equation 2 above was applied to evaluate the Yt laser dose and achieve the specified temperature.

Number

[0107] Here, μ a corresponds to the absorption coefficient at 1.07 μm (about 0.1 cm -1 ), the fluence was calculated for a spot size of 120 μm, and ρ and C are the density and specific heat of the tissue (both of whose product results in about 0.004 J / mm 3 / K). The pulse duration and peak power of the Yt laser were such that ΔT AIt was adjusted to provide calculated temperature rises of 10, 20, 32.5, 65, and 85 °C. The limited peak power of the Yt laser module is 3,000 W (10% maximum duty cycle, 300 W average), and the repetition rate and pulse duration are fixed at 50 μs / 100 μs / 125 μs according to the temperature rise requirements, and the repetition rate is adjusted to account for the 10% duty cycle limit (2,000 Hz, 1,000 Hz, and 800 Hz for 50 / 100 / 125 μs, respectively).

Table 1

[0108] Porcine skin (n = 2, 4 locations per sample) and porcine cartilage (n = 2, 4 locations per sample) samples were utilized to test the configuration of the dual-wavelength Yt / Tm laser by first performing a defect induction step (step A) using a Yt fiber laser (1.07 μm), followed by bubble generation (step B) using a Tm laser (1.94 μm, 300 μJ pulse energy, 100 nanosecond pulse duration, 50 kHz repetition rate for a 5 μs duration). The time delay between the defect induction step and the bubble generation step was fixed such that the Tm pulsed laser irradiation followed the Yt laser defect induction step instantaneously (i.e., t A2 = 0). As described in the methods section, the pulse duration and peak power of the Yt laser were adjusted to provide various temperature rises (ΔT A , Table 1) before the bubble generation laser radiation enters the tissue. Figures 24 - 25 show the volumetric tissue removal rate for Tm laser bubble generation obtained for different ΔT A induced in the defect induction step (step A) resulting from Yt laser irradiation. ΔT ADefect-induced temperature rises between 30 - 50 °C resulted in higher tissue removal rates for a fixed Tm bubble generation pulse energy. Higher defect-induced temperature rises resulted in less effective tissue removal rates. The measured tissue Tm removal rates in these examples were close to the values calculated from the modeling results [4]. Cartilage, which is mechanically stiffer than skin (i.e., has a higher elastic modulus), produced overall lower removal rates compared to skin, but had a similar water content (moisture content) (from simulation results of 70% water content tissue obtained from [4] for a uniform gelatin phantom). From previously reported studies [7, 8, 18] on the temperature dependence of the bulk elastic modulus in cartilage (e.g., the shear elastic modulus in soft tissue in particular), the defect-induced step (step A) generates a non-uniform region of reduced shear elastic modulus corresponding to temperatures in the range of 60 - 70 °C, and thus promotes microcrack and fragmentation propagation to the tissue surface, and following immediately the Tm laser bubble generation step (step B), aids in material ejection. Conservative estimates of the Arrhenius integral (Ω) were calculated assuming a constant temperature up to the thermal relaxation time and are highlighted for the two tissues in FIGS. 24 (porcine cartilage) and 25 (porcine skin) (red arrow Ω>1 and orange arrow Ω>0.1). In actual practice, these estimates will be less conservative due to heat diffusion into the tissue surrounding the defect-induced laser irradiation spot (the threshold temperatures for Ω = 0.1 and Ω = 1 will be higher than those presented in FIGS. 24 - 25). High aspect ratio porcine skin tissue removal (FIG. 26) is enabled by the successive application of repeated defect induction (step A, Yt laser) followed by bubble generation (step B, Tm laser) steps.

[0109] The image of the pre-operative vascular network (Panel A, Figure 27) was overlaid on the post-coagulation angiography image (Panel B) showing a clear coagulation margin. The Yt laser defect induction step (Step A) followed by Tm laser bubble generation (Step B). The post-coagulation subtractive material treatment using Step A resulted in consistent material ejection and cutting during surgery, while the surgical field remained bloodless. The dimensions of the vertical channels generated in the tissue using the defect induction and bubble generation steps with OCT matched the values determined from histology (Figures 27-28). The defect induction step (Step A) followed by bubble generation (Step B) enabled the generation of vertical channels with little observable thermal damage.

[0110] The methodology of the laser defect induction step (Step A) followed by the bubble generation step (Step B) was also tested for in-vivo surgical applications using a fiber catheter by combining both Yt (1.07 μm) and Tm laser (1.94 μm) radiation in a single multimode optical fiber. For Tm laser radiation, the fluence rate at the fiber tip was reduced by a factor of 10 compared to an open bulk optical system, although the fluence value slightly exceeded the threshold for bubble generation. Tm light emerging from a fiber with a 10 μm core size was coupled into a 200 μm core diameter fiber with a reduced fluence rate at the fiber tip (with 80-90% coupling efficiency), while Yt light (50 μm fiber) was coupled with an efficiency slightly lower at about 70% (Figure 29, bottom).

[0111] An in vivo biocompatible glass fiber implementation for tissue subtractive processing using a 200 μm core fiber that provides a lower fluence rate for the bubble generation step (step B) provided material ejection and successful tissue removal for surgery (Figure 30). Post-surgical angiography images (panel B, Figure 30) show a photomontage of Yt laser (1.07 μm) vascular coagulation compared to pre-surgical angiography (panel A, Figure 30). Removal of mouse brain tissue (#C7) took longer than the open system due to a lower bubble generation fluence rate that resulted in a smaller tissue removal rate.

[0112] The co-propagation of defect-inducing and bubble-generating beams on the same line has been successfully demonstrated, and several other embodiments that can be obtained from the results presented above are also recognized. As described above, with respect to tissues, the wavelength options enable combinations of multiple laser wavelengths for the defect-inducing (step A) and bubble-generating (step B) steps. Some combinations of lasers for surgery in biological tissues include Yt (step A, 1.07 μm) / Tm (step B, 1.94 μm), Yt (step A, 1.07 μm) / Ho (step B, 2.06 μm), Er:glass (step A, 1.55 μm) / Tm (step B, 1.94 μm), Er:glass (step A, 1.55 μm) / Ho (step B, 2.06 μm), Tm (step A, 1.94 μm) / Ho (step B, 2.06 μm), in-band Tm / Ho

[19] (pump within the step A band at 1.9 μm, output laser pulse at 2 μm for step B). Those skilled in laser tissue interaction may recognize other possible combinations of lasers. For these combinations, the design of the temporal intensity and timing is completed in a manner similar to the Yt / Tm step for both defect induction and bubble generation. Other combinations can also be envisioned within the 2 μm mid-infrared spectral region in addition to these 2 μm IR regions. Instead of using an IR laser (e.g., Tm or Ho or wavelength-matched Tm) for the bubble-generating step, embodiments also use a short-pulse laser (picosecond to femtosecond) source that has little linear absorption but has sufficient fluence for nonlinear absorption near the focus to generate plasma and bubbles. This approach using the non-linear bubble generation step can better preserve the tissue taken because the irreversible damage will be confined to the region where the bubbles are generated. Complementary to the bubble-inducing step using short-pulse laser radiation (picosecond to femtosecond) is the defect-inducing step that generates a spatially patterned temperature rise. The spatial patterning of the defect-inducing step enables microcrack expansion and fracture propagation to be spatially confined to selected regions within the target material.For example, using an axicon for the defect induction step can be configured to generate a conical region with a constrained surface such that crack propagation and material ejection are spatially controlled and limited to the conical region (FIG. 31). An axicon configuration combined with bubble generation, multiphoton absorption, and plasma generation using a short pulse laser can provide material ejection with minimal thermal modification to a relatively large tissue volume. This configuration can be useful for tissue sampling or fine biopsy such that a diagnostic screening approach can be applied to characterize the tissue sampled.

[0113] Other spatial patterning embodiments enable an array of laser irradiation sites (scanning or microlens array) with collinear propagation of defect induction and bubble generation beams such that a relatively large bubble generation pulse energy can be distributed across the environment - material interface along with the defect induction step. The spatial patterning of the defect induction laser radiation (up to the time of ablation or when the bubbles expand and / or collapse) and the depth profile of the viscoelastic modulus reduction enable microcrack generation and crack propagation along controlled channels and accelerate resection along these channels of the patterned irradiation. Spatial patterning (grid pattern irradiation) is possible for the defect induction step and enables material ejection only at the grid points while the entire region is irradiated by the bubble generation light source (panel C, FIG. 26 through a scanning or microlens array). A large number of spatial patterning geometries can be envisioned where material ejection is enabled by controlling the spatial patterning of the laser irradiation utilized in the defect induction step.

[0114] All of the devices, systems, and / or methods disclosed and claimed in this specification can be made and executed without undue experimentation in light of this disclosure. The devices, systems, and methods of the present invention are described from the perspective of specific embodiments, but it will be apparent to those skilled in the art that variations can be applied to the devices, systems, and / or methods in the steps or series of steps of the methods described herein without departing from the concept, spirit, and scope of the present invention. All such similar substitutions and modifications that are apparent to those skilled in the art are considered to be within the spirit, concept, and scope of the present invention as defined by the appended claims. (References)

[0115] The contents of the following references are hereby incorporated by reference into this specification. [Table 2-1] [Table 2-2]

Claims

1. A system for subtractive material processing, the system comprising: means for performing a defect induction step; means for performing a bubble generation step and wherein the means for performing the defect induction step generates a spatially constrained region with a reduced mechanical modulus in the material near the bubble generation site by directing electromagnetic radiation from the environment onto the material, causing an increase in the defect induction temperature of 30°C to 50°C, thereby reducing the mechanical modulus of the material; wherein the means for performing the bubble generation step generates subsurface bubbles below the environment-material interface by directing pulsed electromagnetic radiation from the environment onto the material after the means for performing the defect induction step has directed electromagnetic radiation from the environment onto the material; A system in which material breakage occurs due to bubble expansion, the material breakage being enhanced by the spatially constrained region with the reduced mechanical modulus generated by the defect induction step, resulting in material ejection.

2. The system according to claim 1, further comprising means for cooling the material before, during, or after the bubble generation step.

3. The system according to claim 1, wherein the material is biological tissue.

4. The system according to claim 3, wherein the biological tissue includes structural inhomogeneities.

5. The system according to claim 4, wherein the structural inhomogeneity is an epithelial tissue layer.

6. The system according to claim 1, wherein the means for performing the bubble generation step generates plasma.

7. The system according to claim 6, wherein the means for performing the bubble generation step comprises an ultrafast laser configured to emit electromagnetic radiation so as to generate the subsurface bubbles in the material.

8. The system according to claim 1, wherein the means for performing the bubble generation step comprises an electromagnetic radiation source, and the means for performing the defect induction step utilizes the electromagnetic radiation obtained from the electromagnetic radiation source.

9. The system according to claim 8, wherein the electromagnetic radiation utilized by the means for performing the defect induction step is obtained from the electromagnetic radiation source through a non-linear conversion process.

10. The means for performing the defect induction step is the system according to claim 3, which utilizes electromagnetic radiation of 0.8 μm to 2.3 μm. **Claim 11** The means for performing the defect induction step is the system according to claim 3, which utilizes electromagnetic radiation of 0.4 μm to 2.3 μm. **Claim 12** The means for performing the defect induction step is the system according to claim 3, which comprises a ytterbium (Yt) fiber laser. **Claim 13** The means for performing the defect induction step is the system according to claim 3, which comprises an erbium (Er): glass laser. **Claim 14** The means for performing the bubble generation step is the system according to claim 3, which comprises a thulium (Tm) laser. **Claim 15** The means for performing the bubble generation step is the system according to claim 3, which comprises a holmium (Ho): YAG laser.

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