Coupling lithium to substrate

Abstract

Neutron generating targets and methods for making neutron generating targets, for example for use in boron neutron capture therapy ("BNCT"). The present specification describes a lithium-containing neutron generating target that can be used to generate a neutron beam to bombard a boron-containing compound in boron neutron capture therapy for cancer. A method includes pressing a lithium foil to a substrate with sufficient force such that lithium deforms and adheres to the substrate during a pressing operation, thereby forming a thin lithium layer on a surface of the substrate.

Description

Technical Field

[0001] The present specification generally relates to methods of coupling a lithium layer to a substrate and using the methods to make neutron-generating targets. Background Art

[0002] Cancer is one of the leading causes of death in contemporary society. According to the Center for Disease Control, the death rate due to cancer in 2020 was 144 per 100,000 people. Locally aggressive malignancies, such as brain cancer, head and neck cancer, and cutaneous and extracutaneous melanoma, are of particular concern because effective means to treat or inhibit the growth of these cancers are limited. For example, boron neutron capture therapy, or BNCT, uses an accelerator-based neutron source to generate short-lived alpha particles from boron-10 that accumulates in a patient's tumor tissue. These alpha particles selectively kill tumor cells while avoiding any damage to healthy organs and tissues. Summary of the invention

[0003] The present specification describes, inter alia, lithium-containing neutron generating targets that can be used to generate neutron beams to bombard boron-containing compounds in boron neutron capture therapy ("BNCT") for cancer. The present invention is based, at least in part, on the recognition that mechanical forces applied to a thin solid lithium film deposited on the surface of a target substrate produce a well-adhered lithium layer of a desired thickness (e.g., 100 μm) on the substrate surface. In one example, prior to depositing the lithium film (or alternatively, foil) onto the substrate, the surface of the substrate is coated with an intermediate layer (e.g., a pure Al layer) that promotes and aids adhesion of the lithium film to the substrate. Advantageously, the method of the present disclosure takes less time and energy than conventional techniques for making lithium-containing targets, which include evaporating and condensing lithium metal on a substrate surface to produce a target. Using the method of the present disclosure produces a neutron generating target having a clean lithium layer of a desired thickness adhered to the substrate surface, which can be obtained quickly, cheaply, and efficiently.

[0004] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those of ordinary skill in the art to which this specification belongs. Methods and materials for use in this application are described herein; other suitable methods and materials known in the art may also be used. The materials, methods and examples are illustrative only and are not intended to be limiting. All publications, patent applications, patents, sequences, database entries and other references mentioned herein are incorporated by reference in their entirety. In the event of a conflict, the present specification (including definitions) shall prevail.

[0005] Other features and advantages of the application will be apparent from the following detailed description and drawings, and from the claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0006] Figure 1A is a high-level schematic of the beamlet system in the example.

[0007] Figure 1B is a more detailed schematic diagram of the beamlet system in the example.

[0008] Figure 2 is a cross-sectional view of an example target assembly subsystem.

[0009] Figure 3A , 3B 3C are cross-sectional views, front perspective views, and rear perspective views of a neutron generation target in an example.

[0010] Figure 4A is a flow chart of an example process for fabricating a neutron generating target by applying mechanical force to a lithium foil positioned on top of a substrate.

[0011] Figure 4B is a cross-sectional view of an example combination of lithium foil and substrate for assembly into a neutron generating target.

[0012] Figure 4C is a flow chart of another example process for fabricating a neutron generating target by preparing a substrate and a lithium foil and then applying a mechanical force to the lithium foil positioned on top of the substrate.

[0013] Figure 5A is a flow chart of an example process for fabricating a neutron generating target by applying mechanical force to a lithium foil over an intermediate precursor layer positioned on top of a substrate.

[0014] Figure 5B is a cross-sectional view of an example combination of a lithium foil and a substrate with an intermediate precursor layer for assembly into a neutron generating target.

[0015] Figure 5C is a cross-sectional view of an example neutron generation target prepared by pressing a lithium foil onto a substrate with an intermediate precursor layer.

[0016] Figure 5D is a flow chart of another example process for fabricating a neutron generating target by preparing a substrate, an intermediate layer, and a lithium foil and then applying a mechanical force to the lithium foil over the intermediate pre-layer positioned on top of the substrate.

[0017] Fig. 6A is a flow chart of an example process for fabricating a neutron generating target by applying mechanical force to a lithium foil over a lithium precursor layer positioned on top of a substrate.

[0018] Figure 6Bis a cross-sectional view of an example combination of a lithium foil and a substrate with a lithium precursor layer for assembly into a neutron generating target.

[0019] Figure 6C is a cross-sectional view of an example neutron generation target prepared by pressing a lithium foil onto a substrate with an intermediate lithium precursor layer.

[0020] Fig.6D is a flow chart of another example process for fabricating a neutron generating target by preparing a substrate, a lithium precursor layer, and a lithium foil, and then applying a mechanical force to the lithium foil over the lithium precursor layer positioned on top of the substrate.

[0021] In the drawings, like reference numerals denote like elements. DETAILED DESCRIPTION

[0022] The lithium coupling technology described in this specification can be used in various applications, in which it is desired to attach a lithium layer to a substrate, such as by mechanical force to adhere the lithium layer to the substrate. The lithium coupling substrate can be used for both medical applications and non-medical applications. Suitable examples of non-medical applications include fusion reactors, scientific tools for nuclear physics research (e.g., Faraday cups for capturing charged particles in a vacuum), industrial manufacturing processes, beam systems for changing material properties (e.g., surface treatment and transmutation), beam systems for irradiating food, and non-medical imaging applications (e.g., cargo or container inspection). Suitable examples of medical applications include beam systems for pathogen destruction and medical sterilization, medical diagnostic systems, medical imaging systems, and radiotherapy systems (e.g., X-ray machines, cobalt-60 therapy machines, linear accelerators, proton beam machines, and neutron beam machines). An example of a medical application of a lithium-coupled substrate is as a neutron generation target for boron neutron capture therapy ("BNCT").

[0023] In general, BNCT is a method for treating many types of cancer, including the most difficult types. Examples of such cancers include liver cancer (including liver metastasis), oral cancer, colon cancer, brain cancer (such as glioblastoma), head and neck cancer, lung cancer, extensive squamous cell carcinoma, laryngeal cancer and melanoma. BNCT is a technique that selectively aims to treat tumor cells while leaving normal cells unharmed using chemical compounds containing the non-radioactive isotope boron-10 with a high tendency to capture low-energy "thermal" neutrons. In this technique, a boron-containing compound is administered to a patient (e.g., by injecting a parenteral composition into a patient's blood vessel) so that boron-10 selectively accumulates in tumor cells. Suitable examples of boron delivery agents that can be administered to cancer patients include boronated amino acids, boron nitride nanotubes, liposomes and immunoliposomes carrying boron particles, various boron-containing nanoparticles, boronated cyclic peptides or acyclic peptides with affinity for cancer cells (e.g., boronated arginylglycyl aspartate, "RGD" or cyclic versions thereof), boronated compounds with affinity for receptors overexpressed in cancer cells, boronated sugars, and boric acids. In general, these compounds are capable of selectively accumulating within malignant tumors while avoiding healthy tissues (e.g., at least about 85 wt.%, at least about 90 wt.%, at least about 95 wt.%, or at least about 99 wt.% of the boron compound accumulates in tumor tissues and not in healthy tissues). For example, upon administration of a boron carrier compound, a therapeutic efficacy of about 20-50 μg of the drug can be obtained. 10 B / g tumor. The tumor boron concentration can be determined by any method generally known for this purpose (e.g., imaging, calibration and / or biopsy). Once a sufficient amount of boron-10 has been collected within the tumor, the patient receives radiation in the form of a neutron beam at or near the tumor site.

[0024] Typically, to generate a neutron beam, protons or other charged particles with sufficient energy (e.g., Li+ with energy above 1.88 MeV) are used. 7 →Be 7 The neutron generation reaction can be described as follows, where p represents protons and n represents neutrons:

[0025] Li 7 (3p,4n)+p=Be 7 (4p,3n)+n

[0026] The resulting neutron beam is moderated and focused on the patient, where the neutrons react with boron-10 in tumor cells to generate short-range alpha particles (He) that selectively kill tumor cells. 4 ):

[0027] B 10(5p,5n)+n=Li 7 (3p,4n)+He 4 (2p,2n)

[0028] This specification describes a lithium-containing neutron generation target that can be used to generate a neutron beam to bombard a boron-containing compound administered to a patient during BNCT. Figure 1A A schematic diagram of an example of a neutron beam system 10 that may be used to generate neutrons for BNCT using the lithium-containing neutron generation targets of the present disclosure.

[0029] like Figure 1A As shown, the beam system 10 includes a hydrogen ion source 12, a low energy beam line ("LEBL") 14, an accelerator 16 coupled to the LEBL 14, and a high energy beam line ("HEBL") 16 extending from the accelerator 16 to a target 100. The LEBL 14 is configured to transmit a negative hydrogen ion beam from the ion source 12 to an input end of the accelerator 16, and the accelerator is configured to generate a proton beam by accelerating the hydrogen ion beam transmitted by the LEBL 14. The HEBL 18 transmits the proton beam from the output end of the accelerator 16 to the target 100. After being bombarded by protons of sufficient energy, the target 100 generates a neutron beam, which is further directed to a tumor site (not shown) in a patient's body.

[0030] Figure 1B 1 is a more detailed schematic diagram of a neutron beam system 10 for boron neutron capture therapy (BNCT). Here, the source 12 is an ion source and the accelerator 16 is a tandem accelerator. The system 10 includes a pre-accelerator system 20 used as a charged particle beam injector, a high voltage (HV) tandem accelerator 16 coupled to the pre-accelerator system 20, and a HEBL 18 extending from the tandem accelerator 16 to a neutron target assembly 200 containing a target (not shown). The pre-accelerator system 20 is configured to deliver a hydrogen ion beam from the ion source 12 to an input end (e.g., an input aperture) of the tandem accelerator 16, and thus also acts as a LEBL 14. The tandem accelerator 16, powered by a high voltage power supply 42 coupled thereto, can produce a proton beam having an energy generally equal to twice the voltage applied to an accelerating electrode positioned within the accelerator 16. The energy level of the proton beam can be achieved by accelerating a beam of negative hydrogen ions from the input end of the accelerator 16 to the innermost high potential electrode, stripping two electrons from each ion, and then accelerating the resulting proton beam downstream with the same applied voltage.

[0031] The HEBL 18 can transmit the proton beam from the output of the accelerator 16 to a target within a neutron target assembly 200, which is positioned at the end of a branch 70 of a beam line extending to a patient treatment room. The system 10 can be configured to direct the proton beam to any number of one or more targets and associated treatment areas. The HEBL 18 shown includes three branches 70, 80, and 90, which can extend to three different patient treatment rooms, wherein each branch can terminate at a target assembly 200 and a downstream beam shaping device (not shown). The HEBL 18 can include a pump chamber 51, quadrupole magnets 52 and 72 to prevent beam defocusing, dipole or bending magnets 56 and 58 to direct the beam to the corresponding target assembly, a beam corrector 53; diagnostic devices (such as current monitors 54 and 76), a fast beam position monitor 55 portion, and a scanning magnet 74.

[0032] The design of the HEBL 18 depends on the configuration of the treatment facility (e.g., a single-story configuration of the treatment facility, a two-story configuration of the treatment facility, etc.). The proton beam can be delivered to a target assembly 200 (e.g., located near a treatment room) using bending magnets 56 and 58. A quadrupole magnet 72 can be included to then focus the proton beam to a certain size of the target. The proton beam then passes through one or more scanning magnets 74, which move the proton beam onto the target surface in a desired pattern (e.g., spiral, curved, stepped in rows and columns, combinations thereof, etc.). The proton beam movement can help achieve a smooth and uniform time-averaged distribution of the proton beam on the lithium target, prevent overheating, and allow the lithium layer (e.g., Figure 3A Neutron generation within the lithium layer 110) is shown to be as uniform as possible.

[0033] The beam current is measured by a current monitor 76. The target assembly 200 may be physically separated from the HEBL volume by a gate valve 77. The main function of the gate valve is to separate the vacuum volume of the beamline from the target when loading the target and / or replacing the old target with a new one.

[0034] In this configuration, the beam is not bent 90 degrees by the bending magnet 56, but rather it is directed toward Figure 1B The beam travels to the right of the CT scan and then enters a quadrupole magnet 52 located on the horizontal beamline. Depending on the building and room configuration, the beam can then be bent to the desired angle by another bending magnet 58. Otherwise, the bending magnet 58 can be replaced with a Y-shaped magnet to split the beamline into two directions for two different treatment rooms located on the same floor.

[0035] Figure 2 is a diagram depicting a cross-sectional view of an example target assembly subsystem 201 suitable for use as Figure 1A and Figure 1BTarget assembly subsystem 200 of neutron beam system 10 is shown. Neutron generating target 101 is enclosed between cover 202 of HEBL 18 and vacuum or near vacuum interior region 210. Arrow B shows the direction of the charged particle (e.g., proton) beam that first strikes the face of upstream side 112 of target 101. Cooling of target 101 can be accomplished on opposite downstream side 114 (the side from which neutron beam exits target 101). Cover 202 can be bolted to HEBL 18, thereby providing vacuum seal 206 between target 101 and vacuum region 210 of HEBL 18, and providing watertight seal 205 between target 101 and coolant inlet 204 and outlet 208.

[0036] Example of lithium layer

[0037] Figure 3A is a cross-sectional view depicting an example lithium-containing neutron generation target for BCNT. Figure 3A and Figure 3B 1 and 11 are perspective views of the upstream side 112 and downstream side 114 of the target, respectively. The target includes a lithium neutron generation layer 110. The lithium in this layer can be composed of two stable isotopes, Li 6 and Li 7 Li in naturally occurring lithium materials 7 The amount of the isotope may range from about 90 wt.% to about 99 wt.%, or from about 92 wt.% to about 98 wt.%. In some embodiments, the lithium in layer 110 is rich in Li 7 And the lack of Li 6 , so that the lithium material contains about 99.9 wt.% or about 100 wt.% Li 7 The lithium in layer 110 may also contain other lithium isotopes, such as Li 3 , Li 4 , Li 8 , Li 11 or Li 12 , or its combination with Li 6 and / or Li 7 Any combination of isotopes.

[0038] The lithium layer 110 may be configured as a planar neutron generating layer bonded to the surface 121 of the substrate 120. A proton beam propagating in a direction B (e.g., Figure 1A18) interacts with the layer 110 to produce neutrons, which in turn travel through the substrate 120 and exit from the downstream side 114 of the target. The thickness of the lithium layer 110 (e.g., the distance between the outer surface 302 of the layer 110 and the surface 121 of the substrate 120) can be selected based on the energy of the protons propagating in the direction B. Table 1 shows the range (sometimes called the stopping range) of the average incident proton particle in natural abundance lithium (approximately 92% lithium-7) for several proton energies. The variable "Depth to Threshold" is listed in the right column and represents the average proton slowing down to within the material. 7 Li(p,n) 7 The distance traveled before the threshold energy (about 1.88 MeV) of the Be reaction. After the proton decelerates beyond this threshold energy, it will no longer be able to produce neutrons. For example, for a proton energy of 2.50 megaelectronvolts (MeV), the high-energy proton enters the lithium material and then travels about 90 microns in the lithium until it decelerates to the threshold energy. In this example, if the lithium thickness is less than 90 microns (μm), the neutron yield will be reduced and the lithium material is not used most efficiently. In practice, it is desired that the target for producing neutrons has a sufficiently thick lithium layer, but not so thick that the proton energy drops below the threshold, dissipates too much heat in the lithium, or produces undesirable gamma radiation. For example, for a 2.5 MeV proton beam, a 200 mm thick lithium layer may undesirably dissipate too much heat in the lithium layer.

[0039]

[0040] Table 1

[0041] A suitable thickness of the lithium layer 110 is about 15 μm to about 180 μm, about 20 μm to about 150 μm, about 40 μm to about 120 μm, about 80 μm to about 120 μm, or about 90 μm to about 100 μm. A suitable proton energy is about 2 MeV to about 3 MeV, or about 2.25 MeV to about 2.75 MeV. In a suitable pairing, the proton energy is about 2.5 MeV, and the thickness of the lithium layer on the substrate surface is about 90 μm or about 100 μm.

[0042] Examples of target substrates

[0043] The substrate 120 may be configured to remove heat to dissipate the high energy level of the incident proton beam. As described above, the thickness of the lithium layer 110 is configured such that the thickness of the lithium layer allows the protons to be heated to form neutrons before the proton energy is reduced to Li 7 (p,n)Be 7After the protons are below the threshold of the reaction (e.g., the threshold for lithium-7 is 1.88 MeV), they relatively quickly or immediately leave the layer 110. This avoids additional energy dissipation in the layer 110, which is inefficient and causes the layer 110 to heat up without generating neutrons. The protons at about the threshold energy level penetrate the substrate 120 and dissipate their remaining energy in the substrate 120, or dissipate partly in the substrate 120 and partly in one or more other components located downstream of the target.

[0044] The substrate 120 may be made of a material having a high thermal conductivity. Suitable values ​​of the thermal conductivity of the substrate 120 include values ​​higher than 300 W×m -1 ×K -1 , higher than 400W×m -1 ×K -1 Or higher than 500W×m -1 ×K -1 , or about 400W×m -1 ×K -1 About 1000W×m -1 ×K -1 . The substrate material can be copper (Cu). Other suitable substrate materials include copper alloys, beryllium, chemical vapor deposited (CVD) diamond, or copper-diamond powder composites. The target can include one or more materials that inhibit blistering, such as a tantalum layer between the lithium layer 110 and the substrate 120. Protons that leave the lithium layer and are deposited in the substrate 120 can generate a significant heat load in the substrate. For example, at an energy level of 2.5 MeV, the leaving protons generate a heat load of about 20 kW to about 25 kW. Therefore, the substrate is actively cooled by a constant coolant flow. For example, the substrate 120 can contain a spiral channel 122, such as Figure 3B Depicted, or containing channels of any other size and configuration as desired. Suitable examples of coolants include water, ethanol, methanol, ethylene glycol, propylene glycol, or any mixture thereof. By cooling the substrate, the substrate temperature during proton bombardment can be controlled so that it does not exceed the melting point of lithium (e.g., about 180°C to about 182°C). In some instances, the substrate temperature during operation is cooled so as not to exceed 100°C. In certain instances, the target is a circular target, which is a plate with a diameter of about 4 inches to about 8 inches (e.g., about 6 inches). The thickness of the target substrate can be about 6 mm to about 12 mm, about 8 mm to about 12 mm, such as about 8 mm. In some instances, the substrate is about 50 times, about 60 times, about 70 times, about 80 times, about 90 times, or about 100 times thicker than the lithium layer in the target or more.

[0045] In some examples, a protective layer (e.g., a passivation region) can be positioned on the lithium layer 110 (e.g., in contact with the surface 302 of the lithium layer 110). Certain examples of passivation materials, as well as their thicknesses and other characteristics, are described in PCT Publication No. WO 2022 / 212821 A1, which is incorporated herein by reference in its entirety. Example passivation materials include lithium fluoride, lithium sulfide, magnesium fluoride, carbon (C), diamond-like carbon, nanocrystalline diamond, polymers, and combinations thereof.

[0046] Example of a method of adhering a lithium layer to a substrate

[0047] Although lithium is a valuable neutron-generating material, there are significant difficulties in depositing a clean lithium layer of desired thickness on a target substrate. Lithium is a highly reactive and corrosive metal that is difficult to handle under normal environmental conditions (e.g., air at room temperature, such as air found in a general laboratory space, etc.). Lithium reacts violently with moisture, nitrogen and / or oxygen in the atmosphere and quickly loses its luster and / or oxidizes. When exposed to the atmosphere, lithium is converted into nitrides (Li3N), hydroxides (LiOH and LiOH-H2O), oxides (Li2O) or carbonates (Li2CO3, the result of a secondary reaction between LiOH and CO2), or any combination of the above. These reaction products can be layered with the substrate in the form of dust, and may prevent pure lithium from attaching to the material of the target substrate (e.g., copper). As used herein, the term "pure" refers to a substantially non-contaminated material (e.g., a metal such as lithium, aluminum, copper or gold). For example, pure lithium is about 99wt.% or more lithium, such as about 99.5wt.% or more lithium.

[0048] Conventionally, in order to avoid the lithium layer being contaminated by its reaction products with air and / or moisture, and in order to promote its attachment to the target substrate, vacuum deposition technology is applied. However, this conventional method has obvious disadvantages. For example, it takes a long time (e.g., up to 24 hours) to evaporate lithium onto the substrate, and involves the use of a heated vacuum evaporator. In addition, it is difficult to control the position where the evaporated gaseous lithium condenses in the vacuum chamber. Therefore, after condensation and cooling time, solid lithium metal covers all surfaces of the chamber, which requires additional time and cost to recycle the lithium not deposited on the target substrate. In addition, using vapor deposition technology, it is difficult to accurately control the thickness of the lithium layer formed on the substrate surface, which is an important parameter (as discussed above) in the neutron generation process.

[0049] Figure 4Ais a flow chart of an example process 400 for manufacturing a neutron generating target. The process involves contacting a surface of a lithium foil with a surface of a substrate (406). In some examples, the contact is continuous (e.g., a continuous and uninterrupted contact is created between a first surface of the lithium foil and the surface of the substrate). In certain examples, a continuous contact is created between the surface of the lithium foil and the surface of the substrate such that 99% or more of a macroscopic area of ​​the surface of the lithium foil is in continuous and / or uninterrupted contact with a corresponding amount of area of ​​the surface of the substrate. This can be achieved by spreading a desired thickness (e.g., 100 μm) of lithium foil on the surface of the substrate and pressing the lithium foil against the substrate to create contact (e.g., continuous contact) between the two surfaces.

[0050] In some examples, a free-standing foil or a foil on a support (e.g., a plastic support) is produced and applied to a substrate. Such foils can be made by "calendering" a volume of lithium, typically involving crushing the lithium between two precision rollers to produce a foil of the desired thickness. This crushing process can be repeated multiple times until a foil of the desired thickness and width is achieved.

[0051] A mechanical force (408) is applied to the lithium foil to press it onto the substrate. The mechanical force can be applied, for example, using a hydraulic press or similar machinery. In some cases, the mechanical force is about 1 megapascal (MPa) to about 3MPa. In such cases, suitable values ​​of the mechanical force include about 1MPa, about 1.5MPa, about 2MPa, about 2.5MPa, or about 3MPa. In some instances, the mechanical force is equal to or higher than the compressive stress of lithium (e.g., about 2MPa). In some cases, a manual application foil can be provided, and pressure is applied manually. A pressure range of 5 kilopascals (kPa) to 500kPa is sufficient (e.g., a pressure of 5kPa to 50kPa, 5kPa to 15kPa). Steps 406 and 408 of process 400 can be performed using two separate devices. For example, in step 406, the desired contact between the two surfaces can be made manually (e.g., in a glove box) or using a manual or automated tool or instrument (e.g., a robotic arm), and in step 408, mechanical force can be applied after contact using a second (separate) tool or instrument (e.g., a mechanical press) to achieve adhesion of the lithium to the substrate. In some examples, steps 406 and 408 of process 400 are performed using the same tool or machine. For example, a single instrument or device can be configured to achieve contact between the lithium foil and the substrate in step 406 and to apply mechanical force to the lithium foil to achieve adhesion. An example of such an instrument is a mechanical press equipped with a robotic arm.

[0052] Figure 4C4 is a flow chart of another example process 405 for manufacturing a neutron generating target. Process 405 includes roughening the surface of a substrate (401). Process 405 also includes etching (402) the surface of the substrate. Etching (402) is performed after roughening the surface. Etching can be performed using an acid, such as an organic acid or an inorganic acid. Examples of organic acids that can be used in the etching process include acetic acid, pyruvic acid, citric acid, oxalic acid, succinic acid, and tartaric acid. Examples of inorganic acids that can be used include hydrochloric acid, nitric acid, hydrofluoric acid, phosphoric acid, and sulfuric acid. Etching can also be performed by heating the surface of the substrate in an atmosphere of hydrogen or other chemically reactive gases, and / or by dry etching, which is also referred to as plasma etching in the semiconductor industry. In the latter process, the surface is cleaned by a chemical reaction between an etching substance (such as charged ions of argon, hydrogen, oxygen, or fluorine, or free radicals generated by these gases in a plasma) and impurities on the surface of the substrate. Without being bound by any theory, it is believed that the plasma activated atoms, free radicals and ions decompose organic and inorganic contaminants like sandblasting to form H2O, CO, CO2 and other volatile products that are easily removed from the surface.

[0053] The process (405) also includes removing (404) contamination from the first surface of the lithium foil (e.g., cleaning or roughening the first surface) to ensure that the exposed surface is sufficiently pure lithium. Since lithium metal is very reactive, the cleaning is performed in an atmosphere of an inert gas (e.g., a rare gas such as argon). For example, the surface of the lithium foil can be plasma cleaned in a glove box, at atmospheric pressure, or under vacuum. In process 404, such decontamination can be performed by hot plasma or cold plasma, as described above for the target substrate, but the melting point of lithium must not be exceeded.

[0054] Process 405 also includes steps 406 and 408, as described above with respect to Figure 4A As described. Optionally, each step 401, 402, 404, 406 and 408 of process 405 is performed using a separate device. For example, surface roughening (401), etching the surface (402) and lithium foil decontamination (404) can be performed using three different plasma torches. Lithium is contacted with the substrate (406) can be performed manually or by a robot (e.g., in a glove box), and applying mechanical force (408) can be performed using a separate hydraulic press. Alternatively, any two or more of steps 401, 402, 404, 406 and 408 of manufacturing process 405 can be performed using the same tool or a machine. For example, a single device can be configured and adapted to perform all steps 401, 402, 404, 406 and 408.

[0055] Figure 4B is depicted during manufacturing process 400 or 405 (reference Figure 4A and4C ) is a cross-sectional view of an example intermediate product formed during the contacting lithium step (406) of the substrate 120. In this step, contact is formed between the lithium foil 110 and the surface 121 of the substrate 120 (for example, contact is formed between the first surface 410 of the lithium foil 110 and the surface 121 of the substrate 120). Then, a mechanical force is applied to the second surface 412 of the lithium foil 110 in a direction C perpendicular to the surface 410 and the surface 121 (the second surface 412 is opposite to the first surface 410 of the lithium foil 110).

[0056] The first surface 410 of the lithium foil 110 may be contaminated with a thin layer 414, which is composed of products of the reaction of lithium metal with O2, N2, H2O or CO2, such as Li2O, LiOH, Li2CO3 and Li3N, or any combination thereof, before contacting the surface of the substrate (if such a step is performed, the thin layer 414 can be at least partially removed from the surface 410 during the cleaning step (404)). Although pure lithium metal easily adheres to the material of the substrate, contamination of the lithium foil surface can interfere with lithium-substrate bonding.

[0057] Mechanical force applied to the second surface 412 in the direction C at or near the compressive stress point can cause lithium shear deformation, forcing the pure lithium metal in the foil 110 to break and penetrate the thin layer 414 composed of the contaminating compound (e.g., Li2O, LiOH or Li2CO3), thereby reaching the surface 121 of the substrate 120 and bonding thereto to form a neutron generation target composed of a lithium layer on the surface of the substrate 120.

[0058] In some instances, explosion welding may be used. For example, two metals may be brought together and force from a pressure plate may be applied by detonating an explosive behind the pressure plate. The instantaneous force from the explosion presses the two pieces of metal together, thereby bonding the two materials.

[0059] A hydraulic press and / or a die with a push rod can be used to apply mechanical force in direction C to the second surface 412. The pressing device (e.g., die) can be specifically designed for lithium pressing. Before contacting with lithium, the surface of the die can be prepared (e.g., coated) to allow the die to be successfully separated from the lithium surface after the pressing is completed.

[0060] The mechanical force applied to the surface 412 of the lithium changes the thickness of the lithium foil 110 such that the thickness of the lithium foil 110 after pressing is less than (eg, about 99%, about 95%, about 90%, or about 80%) the thickness of the lithium foil 110 before pressing.

[0061] Figure 5Ais a flow chart of another example of a process 500 for manufacturing a neutron generating target. The process produces (506) a first layer of material capable of forming an alloy with lithium metal (and / or capable of otherwise chemically or physically adhering to lithium metal) on the surface of a substrate. The first layer can be obtained by applying such material to the surface of the substrate. The material can be applied in a vacuum chamber using conventional vapor deposition techniques. Alternatively, the material can be applied by cold plasma spraying the material onto the surface of the substrate. Such spraying can be performed in a glove box or otherwise in an air-free atmosphere such as an inert gas (e.g., argon) atmosphere. Plasma spraying can be performed at atmospheric pressure or under vacuum, depending on the material (e.g., Al or Pd), the desired thickness of the first layer, and other requirements of the process.

[0062] Suitable examples of the material of the first layer include aluminum (Al), silver (Ag), gold (Au), zinc (Zn), bismuth (Bi) and palladium (Pd) or any combination thereof. The material capable of forming an alloy with lithium metal may be pure aluminum (e.g., about 99 wt.% or more, about 99.5 wt.% or more aluminum), or pure gold (e.g., about 99 wt.% or more, about 99.5 wt.% or more gold), or pure palladium (e.g., about 99 wt.% or more, about 99.5 wt.% or more palladium), or an alloy of aluminum and gold, the alloy may have about 50 wt.% or more, about 60 wt.% or more, about 70 wt.% or more, about 80 wt.% or more, or about 90 wt.% or more aluminum, or the alloy may have about 50 wt.% or more, about 60 wt.% or more, about 70 wt.% or more, about 80 wt.% or more, or about 90 wt.% or more gold.

[0063] Other suitable examples of materials for the first layer include chemically active binder materials (e.g., materials that can react with and / or form chemical bonds with the lithium surface). Examples of such materials include Si, SiO2, SiO, Si3N4, C3N4, and other silicon and carbon-based materials suitable for coating the surface, or any mixture or combination thereof.

[0064] For example, it is believed that when SiO2 is used as the first layer 518 ( Figure 5B ) is deposited on the surface of substrate 120, lithium foil 110 chemically adheres to first layer 518 to form layer 526 by the following chemical reaction with lithium metal ( Figure 5C ):

[0065] Li+SiO2=2LiO+Si

[0066] It is believed that when Si is used as the first layer 518 ( Figure 5B) is deposited on the surface of substrate 120, lithium foil 110 chemically adheres to the first layer by any of the following chemical reactions ((i) or (ii)) with lithium metal to form layer 526 ( Figure 5C ):

[0067] (i) Si + 4Li = 4Li4Si (at about 200°C)

[0068] (ii) 2Li + 6Si = Li2Si6 (when the temperature of some Li atoms is about 600°C)

[0069] It is believed that using a chemically active adhesive material as the first layer 518 promotes physical bonding of the lithium foil 110 to the substrate 120 .

[0070] However, other suitable examples of materials for the first layer include materials that can form a buffer layer (or protective layer) as the first layer 518 on the surface of the substrate 120. It is believed that such materials act as both a binder for the lithium layer 110 and a barrier layer to prevent interdiffusion (e.g., alloying) between Li and the substrate material (e.g., copper). Examples of such materials include TiNSi, TiN, TiWN, Cr, Ti, Ta, TaN, Mo, V, LiF, CrLiO2, CrLi2O4, CrLi2O2, and Li-based materials that can be used as electrode materials for Li-based batteries, or any mixture or combination thereof.

[0071] In some examples (e.g., when the first layer 518 is used as a blocking layer / adhesion layer), a combination of suitable materials is used (e.g., layering). For example, the first layer can be a Cr / Ti bilayer. It is believed that lithium metal is insoluble in chromium (e.g., there is essentially no or minimal diffusion of Li into Cr), and at the same time Cr has excellent adhesion to Cu (an example of the material of the substrate 120). Therefore, a Cr sublayer can be deposited on the surface of the Cu substrate, followed by another Ti sublayer deposited on top of the Cr to form the first layer 518. It is believed that such a combination of first layers promotes adhesion of the lithium layer 110 to the substrate 120, and at the same time prevents lithium metal from diffusing into the substrate (e.g., a substrate made of Cu or its alloys). Alternatively, a thin Ta, Mo, or V sublayer can be deposited (instead of titanium) on top of the Cr sublayer.

[0072] In some examples, the first layer material is Pd, and the amount of Pd in ​​the resulting lithium layer of the target is about 0.5 wt.% to about 1 wt.%. In other examples, the first layer material is Al, and the amount of Al in the resulting lithium layer is less than about 10 wt.%. In yet other examples, the first layer material is Au, and the amount of Au in the resulting lithium layer is equal to or less than about 0.1 wt.%.

[0073] The thickness of the first layer 518 can be selected according to the specific requirements of the process. For example, the thickness of the first layer can be about 1 nm to about 5 nm, about 2 nm to about 3 nm, about 10 nm to about 20 nm, about 10 nm to about 50 nm, about 10 nm to about 100 nm, about 0.01 μm to about 0.3 μm, about 0.01 μm to about 0.2 μm, about 0.05 μm to about 0.2 μm, about 0.05 μm to about 0.2 μm, about 0.01 μm to about 0.1 μm or about 0.5 μm to about 1 μm. In some embodiments, the thickness of the first layer is about 0.01 μm, about 0.05 μm, about 0.1 μm or about 0.2 μm. The thickness of the first layer can be selected based on the maximum amount of the first layer material that does not destroy the neutron generation function of the lithium layer. For example, after the neutron generation target is formed in step 512, the amount of the first layer material in the lithium layer can be about 0.1 wt.% to about 10 wt.%, about 0.1 wt.% to about 5 wt.%, about 0.5 wt.% to about 2 wt.%, or about 0.5 wt.% to about 1 wt.%. In some embodiments, the amount of the first layer material in the lithium layer of the neutron generation target is about 0.5 wt.%, about 1 wt.%, about 2 wt.%, about 5 wt.%, or about 10 wt.%.

[0074] The first layer material is preferably selected so that the neutron yield of the target is no less than about 90%, about 80%, or about 75% of the neutron yield produced by a lithium target manufactured without any first layer material. It is believed that some of the metals that make up the first layer, such as Al, Au, or Pd, absorb neutrons produced by the lithium target when the target is bombarded with protons. Therefore, the amount of the first layer material can be carefully selected to allow the lithium foil to effectively adhere to the surface of the substrate while also allowing sufficient neutron yield to reach the tumor site of the patient.

[0075] See also Figure 5A Once the first layer is applied (508) to the surface of the substrate, process 500 contacts (510) the surface of the lithium foil and the first layer on the substrate (e.g., the surface of the first layer). The contacting can be continuous (e.g., as described above, creating a continuous and uninterrupted contact between the first surface of the lithium foil and the surface of the first layer). The contacting step can be performed in a manner similar to step 406 in process 400 described herein.

[0076] refer to Figure 5A As a final step in process 500, a mechanical force (512) may be applied to the lithium foil to press it into the first layer on the substrate. This pressing may be performed in a manner similar to step 408 in process 400 or 405.

[0077] Figure 5B1 is a cross-sectional view of an example intermediate device formed during the combination of lithium foil and substrate fabricated in the manufacture of a neutron generating target. Contact (e.g., continuous contact) is formed between the first surface 516 of the lithium foil 110 and the surface 520 of the first layer 518. It is believed that upon application of a mechanical force (512, Figure 5A ), the material of the first layer 518 diffuses (or dissolves) into the lithium foil 110 to form an alloy, with the result that the lithium foil 110 adheres to the substrate 120 to obtain a neutron generation target containing a lithium layer on the surface of the substrate. In some embodiments, the diffusion coefficient of the first layer material (e.g., Al, Au, or Pd) for lithium is about 1×10 -10 About 1×10 -9 cm 2 / Second.

[0078] Figure 5C A cross section of an example of the obtained target is schematically shown in FIG. Figure 5C , the lithium layer 110 is bonded to the substrate 120 by the first layer material and the lithium alloy 526. As described above, the proportion of the first layer material (e.g., Al) in the combined amount of lithium and the first layer material in the layers 110 and 526 is generally in the range of about 0.1 wt.% to about 10 wt.%. The amount is selected based on the type of the first layer material so that the neutron yield is reduced by no more than about 25% compared to the neutron yield obtained from a target manufactured without the alloy 526.

[0079] Figure 5D 5 is a flow chart of another example process 501 for making a neutron generating target. The process includes roughening a surface of a substrate (502), etching a surface of the substrate (504), and removing (506) contamination from a first surface of a lithium foil (e.g., cleaning or roughening the first surface) to expose lithium. Steps 502, 504, and 506 of process 501 may be performed in the same manner as described above. Figure 4C The corresponding steps 401, 402 and 404 of the process 405 shown are performed in a similar manner. Figure 5D , process 501 also includes steps 508, 510 and 512, which can be used in conjunction with reference Figure 5ASteps 508, 510, and 512 of the described process 500 are performed in a similar manner. Optionally, process 501 also includes heating (514) the neutron generation target produced during step 512. The heating can reach a temperature below the melting point of lithium (e.g., to a temperature below 180°C). Heating can have a variety of beneficial effects on the adhesion of lithium to the first layer. For example, heating can increase diffusion between the first layer and the lithium foil. Alternatively or in addition, heating can induce and / or increase alloying between the material of the first layer and the lithium foil. The target can be heated to about 80°C or more, about 100°C or more, about 110°C or more, about 120°C or more, about 130°C or more, about 140°C or more, about 150°C or more, such as about 160°C. The target can be heated for a sufficient amount of time to induce and / or increase diffusion processes and / or induce and / or increase alloying. For example, the target can be heated for about 1 second or longer, about 10 seconds or longer, about 30 seconds or longer, about 1 minute or longer, about 5 minutes or longer, about 10 minutes or longer, or about 30 minutes or longer, such as up to one hour. The target can be heated for the duration of applying (512) the mechanical force.

[0080] Fig. 6A 600 is a flow chart of an example process 600 for making a neutron generating target. The process produces (608) a first layer of lithium on a surface of a substrate. The first layer of lithium can be obtained by applying lithium to the surface of the substrate. Figure 5A Lithium is applied to the surface of the substrate in the manner of applying the first layer as described in step 508 of process 500. The thickness of the first layer of lithium in step 608 can be selected based on the specific needs of the process. For example, the thickness of the first layer of lithium can be about 0.01 μm to about 0.3 μm, about 0.01 μm to about 0.2 μm, about 0.05 μm to about 0.2 μm, about 0.05 μm to about 0.2 μm, or about 0.01 μm to about 0.1 μm. In some embodiments, the thickness of the first layer of lithium in step 608 is about 0.01 μm, about 0.05 μm, about 0.1 μm, or about 0.2 μm. The thickness of the first layer of lithium prepared in step 608 can be selected to allow the lithium foil to effectively adhere to the surface of the substrate.

[0081] Once the first layer has been applied to the surface of the substrate, the process creates (610) contact (e.g., continuous contact) between one surface of the lithium foil and the first layer of lithium on the substrate (e.g., the surface of the first layer of lithium). This step can be performed in a similar manner as described in step 406 of process 400 or step 510 of process 500.

[0082] Then, a mechanical force may be applied to the lithium foil (612) to press it into the first layer on the substrate. This step may be performed in a similar manner to step 408 in process 400 or step 512 in process 500.

[0083] Fig.6D 6 is a flow chart of another example process 601 for making a neutron generating target. Process 601 includes roughening a surface of a substrate (602), etching a surface of the substrate (604), and removing (606) contamination from a first surface of a lithium foil (e.g., cleaning or roughening the first surface) to expose lithium. These steps can be performed in a manner similar to corresponding steps 401, 402, and 404 of process 400, respectively; or in a manner similar to steps 502, 504, and 506 of process 500, respectively.

[0084] Process 601 also includes steps 608, 610, and 612, which can be respectively described in steps 508, 510, and 512 of processes 500 and 501 (see Figure 5A and 5D ). In some embodiments, process 601 further includes a step of heating (614) the neutron generation target during the step of applying mechanical force (612) to promote diffusion between the lithium of the first layer and the lithium foil. This step can be performed in a manner and with parameters similar to step 514 of process 500 described above.

[0085] Figure 6B is Fig. 6A 6 is a cross-sectional view of an example intermediate device formed during step 610 of process 600 (combination of lithium foil and substrate for making a neutron generation target). In this step, contact is formed between the first surface 620 of the lithium foil 110 and the surface 618 of the first layer 616. It is believed that during the application (612) of the mechanical force to the second surface 622 of the lithium foil 110, the lithium of the first layer 616 diffuses (or dissolves) into the lithium foil 110 to form a lithium layer, with the result that the lithium foil 110 adheres to the surface 121 of the substrate 120 to obtain a neutron generation target containing a lithium layer on the surface of the substrate.

[0086] Figure 6C A cross section of an example resulting target is schematically shown in . A lithium layer 624 consisting of lithium and lithium foil 110 forming a first layer 618 adheres to a surface 121 of a substrate 120 due to initial adhesion and bonding of the first lithium layer during deposition of the first layer of lithium on the substrate. Process 601 may also include a step comprising heating (614) the neutron generation target while applying a mechanical force (612) to enhance adhesion between the first layer of lithium and the lithium foil (e.g., by enhancing diffusion) to obtain a continuous lithium layer on the surface of the substrate. As described above, the heating may be to a temperature below the melting point of lithium. This step may be performed in a manner and with parameters similar to step 514 of process 500 described above.

[0087] In some examples, the substrate and / or lithium foil can vibrate (e.g., ultrasonically) when the foil is pressed against the substrate (e.g., with or without the first layer). Vibrating the substrate and / or lithium foil can enhance adhesion between the substrate and the foil, for example, by creating friction between the surfaces. The vibration can be performed while heating the target. In some examples, the frequency of the vibration is in the range of 1 kHz to 100 kHz (e.g., in the range of 5 kHz to 25 kHz).

[0088] Although the above method involves roughening and etching the surface of the substrate to which the lithium layer (and, in some cases, the first layer of another material) adheres, the substrate surface can be treated alternatively or additionally. For example, in some cases, the substrate surface can be cleaned by heating the surface. For example, heating the copper surface sufficiently can clean the copper surface by reducing the surface oxide. The copper substrate is heated to about 300°C or higher, while the substrate is maintained in an inert atmosphere (e.g., argon), and the copper oxide at the substrate surface can be reduced to copper. Generally, any atmosphere that does not contain an element to be eliminated (e.g., oxygen in the form of copper oxide) can be used as a reducing atmosphere. In addition to argon, other possible gases suitable for reducing surface oxides are neon, helium, krypton, xenon, and N2. In some cases, CO2 can be a suitable gas, in which oxygen is more closely combined with oxygen in, for example, copper oxide. Synthetic gas, such as a mixture of an inert gas and hydrogen, can be used. Hydrogen can be used alone at low pressure.

[0089] Typically, heat cleaning may be performed before, after or in place of the roughening and / or etching steps.In addition to the embodiments of the appended claims and the embodiments described above, each of the embodiments in the following numbered paragraphs is also novel.

[0090] Paragraph 1. A method for manufacturing a neutron generation target, the method comprising: (i) bringing a first surface of a lithium foil into contact with a surface of a substrate; and (ii) applying a mechanical force to a second surface of the lithium foil opposite to the first surface of the lithium foil, thereby adhering the first surface of the lithium foil to the surface of the substrate to obtain the neutron generation target comprising a lithium layer on the surface of the substrate.

[0091] Paragraph 2. The method of Paragraph 1, wherein the contacting is continuous.

[0092] Paragraph 3. The method of paragraph 1 or 2, comprising roughening the surface of the substrate before the first surface of the lithium foil contacts the surface of the substrate.

[0093] Paragraph 4. The method of any one of paragraphs 1 to 3, comprising etching the surface of the substrate.

[0094] Paragraph 5. The method of Paragraph 4, wherein etching the surface of the substrate is performed using an acid.

[0095] Paragraph 6. The method of Paragraph 4, wherein etching the surface of the substrate is performed by heating the substrate in the presence of hydrogen.

[0096] Paragraph 7. The method of any of Paragraphs 1 to 6, comprising removing contamination from the first surface of the lithium foil to expose lithium.

[0097] Paragraph 8. A method according to any one of paragraphs 1 to 7, wherein the lithium foil comprises about 92 weight percent (wt.%) to about 98 wt.% Li 7 isotope.

[0098] Paragraph 9. The method according to any one of paragraphs 1 to 8, wherein the thickness of the lithium foil is from about 15 micrometers (μm) to about 180 μm.

[0099] Paragraph 10. The method according to Paragraph 9, wherein the thickness of the lithium foil is from about 90 μm to about 100 μm.

[0100] Paragraph 11. A method according to any one of paragraphs 1 to 10, wherein the thermal conductivity of the substrate is about 300 W×m -1 ×K -1 About 1000W×m -1 ×K -1 .

[0101] Paragraph 12. The method of any of paragraphs 1 to 11, wherein the substrate consists essentially of copper.

[0102] Paragraph 13. The method of any of paragraphs 1 to 11, wherein the substrate comprises diamond.

[0103] Paragraph 14. The method of any of paragraphs 1 to 11, wherein the substrate comprises a copper-diamond powder composite material.

[0104] Paragraph 15. The method of any one of paragraphs 1 to 14, wherein the thickness of the substrate is about 50 times, about 60 times, about 70 times, about 80 times, about 90 times, or about 100 times the thickness of the lithium foil.

[0105] Paragraph 16. The method of any one of paragraphs 1 to 15, wherein the mechanical force is from about 1 megapascal (MPa) to about 3 MPa.

[0106] Paragraph 17. The method according to paragraph 16, wherein the mechanical force is about 2 MPa.

[0107] Paragraph 18. A method for manufacturing a neutron generation target, the method comprising: (i) applying a material to a surface of a substrate to obtain a first layer on the surface of the substrate, wherein the material is capable of forming an alloy with lithium metal or is capable of otherwise chemically or physically adhering to lithium metal; (ii) contacting the first layer with a first surface of a lithium foil; and (iii) applying a mechanical force to a second surface of the lithium foil opposite to the first surface of the lithium foil, thereby causing the first layer to adhere the lithium foil to the substrate to obtain the neutron generation target comprising a lithium layer on the surface of the substrate.

[0108] Paragraph 19. The method of Paragraph 18, wherein the contacting is continuous.

[0109] Paragraph 20. The method according to paragraph 18 further includes heating the neutron generation target while applying the mechanical force to promote diffusion between the material of the first layer and the lithium foil and / or induce alloying therebetween, and / or vibrating the neutron generation target while applying the mechanical force to generate friction between the first layer and the first surface of the lithium foil.

[0110] Paragraph 21. The method of paragraph 18, wherein the heating is performed at a temperature equal to or less than about 180 degrees Celsius (°C).

[0111] Paragraph 22. The method of paragraph 19, wherein the heating is performed at a temperature of about 100°C to about 120°C.

[0112] Paragraph 23. The method of any of paragraphs 18 to 22, comprising roughening the surface of the substrate before applying the material to the surface of the substrate.

[0113] Paragraph 24. The method of Paragraph 23, wherein roughening the surface of the substrate comprises etching the surface of the substrate.

[0114] Paragraph 25. The method of Paragraph 24, wherein etching the surface of the substrate is performed using an acid.

[0115] Paragraph 26. The method of paragraph 24, wherein etching the surface of the substrate is performed by heating the substrate in the presence of hydrogen.

[0116] Paragraph 27. The method of any of paragraphs 18 to 26, comprising removing contamination from the first surface of the lithium foil to expose lithium.

[0117] Paragraph 28. A method according to any one of paragraphs 18 to 27, wherein the lithium foil comprises about 92 weight percent (wt.%) to about 98 wt.% Li 7 isotope.

[0118] Paragraph 29. The method of any of paragraphs 18 to 27, wherein the lithium foil has a thickness of about 15 micrometers (μm) to about 180 μm.

[0119] Paragraph 30. The method of Paragraph 29, wherein the lithium foil has a thickness of about 90 μm to about 100 μm.

[0120] Paragraph 31. A method according to any one of paragraphs 18 to 30, wherein the thermal conductivity of the substrate is about 300 W×m -1 ×K -1 About 1000W×m -1 ×K -1 .

[0121] Paragraph 32. The method of any of paragraphs 18 to 31, wherein the substrate consists essentially of copper.

[0122] Paragraph 33. The method of any of paragraphs 18 to 31, wherein the substrate comprises diamond.

[0123] Paragraph 34. The method of any of paragraphs 18 to 31, wherein the substrate comprises a copper-diamond powder composite material.

[0124] Paragraph 35. The method of any of paragraphs 18 to 34, wherein the thickness of the substrate is about 50 times, about 60 times, about 70 times, about 80 times, about 90 times, or about 100 times the thickness of the lithium foil.

[0125] Paragraph 36. The method of any one of paragraphs 18 to 35, wherein the mechanical force is from about 1 megapascal (MPa) to about 3 MPa.

[0126] Paragraph 37. The method according to paragraph 36, wherein the mechanical force is about 2 MPa.

[0127] Paragraph 38. A method according to any one of paragraphs 18 to 37, wherein the material is substantially composed of: Al, Ag, Au, Zn, Bi, Pd, Si, SiO2, SiO, Si3N4, C3N4, TiNSi, TiN, Cr, Ti, Ta, Mo, V, LiF, CrLiO2, CrLi2O4 or CrLi2O2 or any combination thereof.

[0128] Paragraph 39. The method of paragraph 38, wherein the material consists essentially of aluminum.

[0129] Paragraph 40. The method of any of paragraphs 18 to 39, wherein applying the material comprises vapor depositing or plasma depositing the material onto the surface of the substrate.

[0130] Paragraph 41. The method according to paragraph 40, wherein the vapor deposition or the plasma deposition is performed at atmospheric pressure.

[0131] Paragraph 42. The method according to paragraph 40, wherein the vapor deposition or the plasma deposition is performed under vacuum.

[0132] Paragraph 43. The method of any of paragraphs 18 to 42, wherein the first layer has a thickness of about 0.002 μm to about 1 μm.

[0133] Paragraph 44. The method of Paragraph 43, wherein the first layer has a thickness of about 0.1 μm.

[0134] Paragraph 45. The method of any of paragraphs 18 to 44, wherein the material is capable of forming the alloy in the lithium layer and the amount of the material in the lithium layer of the neutron generating target is about 0.5 wt.% to about 10 wt.%.

[0135] Paragraph 46. A method according to any of paragraphs 18 to 45, wherein the neutron generating target is capable of producing a neutron yield that is not less than 90% of the neutron yield produced by a target prepared without using a material capable of forming an alloy with lithium metal.

[0136] Paragraph 47. A combination of a lithium foil and a substrate for making a neutron generating target, the combination comprising: a substrate; a first layer of material capable of forming an alloy with lithium metal positioned above the substrate, or capable of otherwise chemically or physically adhering to the lithium metal; and a lithium foil; wherein a first surface of the lithium foil is in contact with the first layer.

[0137] Paragraph 48. The combination of paragraph 47, wherein the contact between the lithium foil and the first layer is continuous.

[0138] Paragraph 49. The combination of paragraph 48, wherein the lithium foil comprises about 92 weight percent (wt.%) to about 98 wt.% Li 7 isotope.

[0139] Paragraph 50. The combination according to any of paragraphs 47 to 49, wherein the lithium foil has a thickness of about 15 μm to about 180 μm.

[0140] Paragraph 51. The combination of paragraph 50, wherein the lithium foil has a thickness of about 90 μm to about 100 μm.

[0141] Paragraph 52. The combination according to any one of paragraphs 47 to 51, wherein the thermal conductivity of the substrate is about 300 W×m -1 ×K -1 About 1000W×m -1 ×K -1 .

[0142] Paragraph 53. The combination of any of paragraphs 47 to 52, wherein the substrate consists essentially of copper.

[0143] Paragraph 54. The combination of any one of paragraphs 47 to 52, wherein the substrate comprises diamond.

[0144] Paragraph 55. The combination of any of paragraphs 47 to 52, wherein the substrate comprises a copper-diamond powder composite material.

[0145] Paragraph 56. The combination of any of paragraphs 47 to 55, wherein the thickness of the substrate is about 50 times, about 60 times, about 70 times, about 80 times, about 90 times, or about 100 times the thickness of the lithium foil.

[0146] Paragraph 57. A combination according to any of paragraphs 47 to 56, wherein the material consists essentially of: Al, Ag, Au, Zn, Bi, Pd, Si, SiO2, SiO, Si3N4, C3N4, TiNSi, TiN, TiWN, Cr, Ti, Ta, TaN, Mo, V, LiF, CrLiO2, CrLi2O4 or CrLi2O2 or any combination thereof.

[0147] Paragraph 58. The combination of paragraph 57, wherein the material consists essentially of aluminum.

[0148] Paragraph 59. The combination according to any of paragraphs 47 to 58, wherein the first layer has a thickness of about 0.002 μm to about 1 μm.

[0149] Paragraph 60. The combination of Paragraph 59, wherein the first layer has a thickness of about 0.1 μm.

[0150] Paragraph 61. The combination of any of paragraphs 47 to 60, wherein the amount of the material capable of forming an alloy with lithium metal in the combined amount of the first layer and the lithium foil is from about 0.1 wt.% to about 10 wt.%.

[0151] Paragraph 62. The combination according to paragraph 61, wherein the amount is from about 0.5 wt.% to about 1 wt.%.

[0152] Paragraph 63. A method for manufacturing a neutron generating target for boron neutron capture therapy, the method comprising: (i) applying lithium to a surface of a substrate to obtain a first lithium layer on the surface of the substrate; (ii) bringing the first lithium layer on the surface of the substrate and a first surface of a lithium foil into contact with each other; and (iii) applying a mechanical force sufficient to diffuse lithium from the first layer into the lithium foil and adhere the lithium foil to the substrate to a second surface of the lithium foil opposite to the first surface of the lithium foil to obtain the neutron generating target comprising a lithium layer on the surface of the substrate.

[0153] Paragraph 64. The method of paragraph 63, wherein the contact between the first lithium layer and the first surface of the lithium foil is continuous.

[0154] Paragraph 65. The method according to paragraph 63 further includes heating the neutron generation target during the application of the mechanical force to induce or promote diffusion between the first layer and the lithium foil, and / or vibrating the neutron generation target during the application of the mechanical force to generate friction between the first lithium layer and the first surface of the lithium foil.

[0155] Paragraph 66. The method of paragraph 65, wherein the heating comprises a temperature equal to or less than about 180 degrees Celsius (°C).

[0156] Paragraph 67. The method of paragraph 66, wherein the heating comprises a temperature of about 100°C to about 120°C.

[0157] Paragraph 68. The method of any of paragraphs 63 to 67, comprising roughening the surface of the substrate before applying lithium to the surface of the substrate.

[0158] Paragraph 69. The method of Paragraph 68, comprising etching the surface of the substrate.

[0159] Paragraph 70. The method of Paragraph 69, wherein etching the substrate surface is performed using an acid.

[0160] Paragraph 71. The method of paragraph 69, wherein etching the surface of the substrate is performed by heating the substrate in the presence of hydrogen.

[0161] Paragraph 72. The method of any of paragraphs 63 to 71, comprising removing contamination from the first surface of the lithium foil to expose lithium.

[0162] Paragraph 73. A method according to any one of paragraphs 63 to 72, wherein the lithium foil comprises about 92 weight percent (wt.%) to about 98 wt.% Li 7 isotope.

[0163] Paragraph 74. The method of any of paragraphs 63 to 73, wherein the lithium foil has a thickness of about 15 micrometers (μm) to about 180 μm.

[0164] Paragraph 75. The method according to any one of paragraphs 63 to 74, wherein the thermal conductivity of the substrate is about 300 W×m -1 ×K -1 About 1000W×m -1 ×K -1 .

[0165] Paragraph 76. The method of any of paragraphs 63 to 75, wherein the substrate comprises copper.

[0166] Paragraph 77. The method of any of paragraphs 63 to 75, wherein the substrate comprises diamond.

[0167] Paragraph 78. The method of any of paragraphs 63 to 75, wherein the substrate comprises a copper-diamond powder composite material.

[0168] Paragraph 79. A method according to any of paragraphs 63 to 78, wherein the thickness of the substrate is about 50 times, about 60 times, about 70 times, about 80 times, about 90 times, or about 100 times the thickness of the lithium foil.

[0169] Paragraph 80. The method of any one of paragraphs 63 to 79, wherein the mechanical force is from about 1 megapascal (MPa) to about 3 MPa.

[0170] Paragraph 81. The method according to paragraph 80, wherein the mechanical force is about 2 MPa.

[0171] Paragraph 82. A method according to any one of paragraphs 63 to 81, wherein applying lithium to the surface of the substrate to obtain the first lithium layer on the surface of the substrate comprises vapor depositing or plasma depositing lithium on the surface of the substrate.

[0172] Paragraph 83. The method according to paragraph 82, wherein the vapor deposition or the plasma deposition is performed at atmospheric pressure.

[0173] Paragraph 84. The method according to paragraph 82, wherein the vapor deposition or the plasma deposition is performed under vacuum.

[0174] Paragraph 85. The method of any of paragraphs 63 to 84, wherein the first layer has a thickness of about 0.01 μm to about 0.3 μm.

[0175] Paragraph 86. The method of paragraph 85, wherein the first layer has a thickness of about 0.1 μm.

[0176] Paragraph 87. A method according to paragraph 1 or 2, wherein the first surface of the lithium foil contacts the surface of the substrate such that 99% or more of the macroscopic area of ​​the first surface of the lithium foil contacts a corresponding amount of area of ​​the surface of the substrate.

[0177] Paragraph 88. The method of paragraph 18 or 19, wherein the first surface of the lithium foil contacts the first layer such that 99% or more of a macroscopic area of ​​the first surface of the lithium foil contacts a corresponding amount of area of ​​a surface of the substrate.

[0178] Paragraph 89. The combination of paragraphs 47 or 48, wherein 99% or more of the macroscopic area of ​​the first surface of the lithium foil is in contact with a corresponding amount of area of ​​the surface of the substrate.

[0179] Paragraph 90. The method of paragraph 63 or 64, wherein the first surface of the lithium foil is contacted with the first lithium layer such that 99% or more of a macroscopic area of ​​the first surface of the lithium foil is in contact with the first lithium layer.

[0180] Other embodiments

[0181] It should be understood that although the application has been described in conjunction with the detailed description, the foregoing description is intended to illustrate rather than limit the scope of the application, which is defined by the scope of the appended claims. Other aspects, advantages and modifications are within the scope of the following claims.

[0182] It should be noted that all features, elements, components, functions, and steps described with respect to any embodiment provided herein are intended to be combined and replaced with features, elements, components, functions, and steps from any other embodiment. If a feature, element, component, function, or step is described with respect to only one embodiment, it should be understood that the feature, element, component, function, or step can be used with each of the other embodiments described herein unless otherwise explicitly stated.

Claims

1. A method for manufacturing a neutron generating target, the method comprising: (i) contacting a first surface of the lithium foil with a surface of a substrate; and (ii) applying a mechanical force to a second surface of the lithium foil opposite to the first surface of the lithium foil, thereby adhering the first surface of the lithium foil to the surface of the substrate to obtain the neutron generation target including a lithium layer on the surface of the substrate. The method of claim 1 , wherein the contacting is continuous. 3 . The method according to claim 1 , comprising roughening the surface of the substrate before the first surface of the lithium foil contacts the surface of the substrate. 4 .

4. The method of any one of claims 1 to 3, comprising etching the surface of the substrate. The method of claim 4 , wherein etching the surface of the substrate is performed using an acid.

6. The method of claim 4, wherein etching the surface of the substrate is performed by heating the substrate in the presence of hydrogen.

7. The method of any one of claims 1 to 6, comprising removing contamination from the first surface of the lithium foil to expose lithium.

8. The method of any one of claims 1 to 7, wherein the lithium foil comprises about 92 weight percent (wt.%) to about 98 wt.% Li 7 isotope.

9. The method of any one of claims 1 to 8, wherein the lithium foil has a thickness of about 15 micrometers (μm) to about 180 μm. 10 . The method of claim 9 , wherein the lithium foil has a thickness of about 90 μm to about 100 μm.

11. The method according to any one of claims 1 to 10, wherein the thermal conductivity of the substrate is about 300 W x m -1 ×K -1 About 1000W×m -1 ×K -1 .

12. The method of any one of claims 1 to 11, wherein the substrate consists essentially of copper.

13. The method of any one of claims 1 to 11, wherein the substrate comprises diamond.

14. The method of any one of claims 1 to 11, wherein the substrate comprises a copper-diamond powder composite material.

15. The method of any one of claims 1 to 14, wherein the thickness of the substrate is about 50 times, about 60 times, about 70 times, about 80 times, about 90 times, or about 100 times the thickness of the lithium foil.

16. The method of any one of claims 1 to 15, wherein the mechanical force is from about 1 MegaPascal (MPa) to about 3 MPa.

17. The method of claim 16, wherein the mechanical force is about 2 MPa.

18. A method of manufacturing a neutron generating target, the method comprising: (i) applying a material to a surface of a substrate to obtain a first layer on said surface of said substrate, wherein The material is capable of forming an alloy with lithium metal or is otherwise capable of chemically or physically adhering to lithium metal; (ii) contacting the first layer with a first surface of a lithium foil; as well as (iii) applying a mechanical force to a second surface of the lithium foil opposite to the first surface of the lithium foil, thereby causing the first layer to adhere the lithium foil to the substrate to obtain the neutron generation target including a lithium layer on the surface of the substrate.

19. The method of claim 18, wherein the contacting is continuous.

20. The method of claim 18, further comprising heating the neutron generation target while applying the mechanical force to promote diffusion and / or induce alloying between the material of the first layer and the lithium foil, and / or vibrating the neutron generation target while applying the mechanical force to generate friction between the first layer and the first surface of the lithium foil.

21. The method of claim 18, wherein the heating is performed at a temperature equal to or less than about 180 degrees Celsius (°C).

22. The method of claim 21, wherein the heating is performed at a temperature of about 100°C to about 120°C.

23. A method according to any one of claims 18 to 22 comprising roughening the surface of the substrate before applying the material to the surface of the substrate.

24. The method of claim 23, wherein roughening the surface of the substrate comprises etching the surface of the substrate.

25. The method of claim 24, wherein etching the surface of the substrate is performed using an acid.

26. The method of claim 24, wherein etching the surface of the substrate is performed by heating the substrate in the presence of hydrogen.

27. The method of any one of claims 18 to 26, comprising removing contamination from the first surface of the lithium foil to expose lithium.

28. The method of any one of claims 18 to 27, wherein the lithium foil comprises about 92 weight percent (wt.%) to about 98 wt.% Li 7 isotope.

29. The method of any one of claims 18 to 27, wherein the lithium foil has a thickness of about 15 micrometers (μm) to about 180 μm.

30. The method of claim 29, wherein the lithium foil has a thickness of about 90 μm to about 100 μm.

31. The method of any one of claims 18 to 30, wherein the thermal conductivity of the substrate is about 300 W x m -1 ×K -1 About 1000W×m -1 ×K -1 .

32. The method of any one of claims 18 to 31 , wherein the substrate consists essentially of copper.

33. A method according to any one of claims 18 to 31, wherein the substrate comprises diamond.

34. The method of any one of claims 18 to 31 , wherein the substrate comprises a copper-diamond powder composite material.

35. The method of any one of claims 18 to 34, wherein the thickness of the substrate is about 50 times, about 60 times, about 70 times, about 80 times, about 90 times, or about 100 times the thickness of the lithium foil.

36. The method of any one of claims 18 to 35, wherein the mechanical force is from about 1 MegaPascal (MPa) to about 3 MPa.

37. The method of claim 36, wherein the mechanical force is about 2 MPa.

38. The method of any one of claims 18 to 37, wherein the material consists essentially of: Al, Ag, Au, Zn, Bi, Pd, Si, SiO2, SiO, Si3N4, C3N4, TiNSi, TiN, TiWN, Cr, Ti, Ta, TaN, Mo, V, LiF, CrLiO2, CrLi2O4 or CrLi2O2 or any combination thereof.

39. The method of claim 38, wherein the material consists essentially of aluminum.

40. The method of any one of claims 18 to 39, wherein applying the material comprises vapor depositing or plasma depositing the material onto the surface of the substrate.

41. The method of claim 40, wherein the vapor deposition or the plasma deposition is performed at atmospheric pressure.

42. The method of claim 40, wherein the vapor deposition or the plasma deposition is performed under vacuum.

43. The method of any one of claims 18 to 42, wherein the first layer has a thickness of about 0.002 μm to about 1 μm.

44. The method of claim 43, wherein the first layer has a thickness of about 0.1 μm.

45. The method of any one of claims 18 to 44, wherein the material is capable of forming the alloy in the lithium layer, and the amount of the material in the lithium layer of the neutron generating target is about 0.5 wt.% to about 10 wt.%.

46. ​​The method of any one of claims 18 to 45, wherein the neutron generating target is capable of producing a neutron yield that is not less than 90% of the neutron yield produced by a target prepared without using a material capable of forming an alloy with lithium metal.

47. A combination of a lithium foil and a substrate for making a neutron generating target, the combination comprising: substrate; a first layer of material capable of forming an alloy with, or otherwise chemically or physically adhering to, lithium metal positioned over the substrate; as well as Lithium foil; The first surface of the lithium foil is in contact with the first layer.

48. The combination of claim 47, wherein the contact between the lithium foil and the first layer is continuous.

49. The combination of claim 48, wherein the lithium foil comprises from about 92 weight percent (wt.%) to about 98 wt.% Li 7 isotope.

50. The combination of any one of claims 47 to 49, wherein the lithium foil has a thickness of about 15 μm to about 180 μm.

51. The combination of claim 50, wherein the lithium foil has a thickness of about 90 μm to about 100 μm.

52. The combination of any one of claims 47 to 51, wherein the thermal conductivity of the substrate is about 300 W x m -1 ×K -1 About 1000W×m -1 ×K -1 .

53. The combination of any one of claims 47 to 52, wherein said substrate consists essentially of copper.

54. The combination of any one of claims 47 to 52, wherein the substrate comprises diamond.

55. The combination of any one of claims 47 to 52, wherein the substrate comprises a copper-diamond powder composite material.

56. The combination of any one of claims 47 to 55, wherein the thickness of the substrate is about 50 times, about 60 times, about 70 times, about 80 times, about 90 times, or about 100 times the thickness of the lithium foil.

57. The combination of any one of claims 47 to 56, wherein said material consists essentially of: Al, Ag, Au, Zn, Bi, Pd, Si, SiO2, SiO, Si3N4, C3N4, TiNSi, TiN, Cr, Ti, Ta, Mo, V, LiF, CrLiO2, CrLi2O4 or CrLi2O2 or any combination thereof.

58. The combination of claim 57, wherein said material consists essentially of aluminum.

59. The combination of any one of claims 47 to 58, wherein the thickness of the first layer is from about 0.002 μm to about 1 μm.

60. The combination of claim 59, wherein the first layer has a thickness of about 0.1 μm.

61. The combination of any one of claims 47 to 60, wherein the amount of said material capable of forming an alloy with lithium metal in the combined amount of said first layer and said lithium foil is from about 0.1 wt.% to about 10 wt.%.

62. The combination according to claim 61, wherein said amount is from about 0.5 wt.% to about 1 wt.%.

63. A method of making a neutron generating target for use in boron neutron capture therapy, the method comprising: (i) applying lithium to a surface of a substrate to obtain a first lithium layer on the surface of the substrate; (ii) bringing the first lithium layer on the first surface of the substrate and the first surface of the lithium foil into contact with each other; as well as (iii) applying a mechanical force sufficient to diffuse lithium from the first layer into the lithium foil and adhere the lithium foil to the substrate to obtain the neutron generation target including a lithium layer on the surface of the substrate, to a second surface of the lithium foil opposite to the first surface of the lithium foil.

64. The method of claim 63, wherein the contact between the first lithium layer and the first surface of the lithium foil is continuous.

65. The method of claim 63, further comprising heating the neutron generation target during the applying of the mechanical force to induce or promote diffusion between the first layer and the lithium foil, and / or vibrating the neutron generation target during the applying of the mechanical force to generate friction between the first lithium layer and the first surface of the lithium foil.

66. The method of claim 65, wherein the heating comprises a temperature at or below about 180 degrees Celsius (°C).

67. The method of claim 66, wherein the heating comprises a temperature of about 100°C to about 120°C.

68. A method according to any one of claims 63 to 67 comprising roughening the surface of the substrate before applying lithium to the surface of the substrate.

69. The method of claim 68, comprising etching the surface of the substrate.

70. The method of claim 69, wherein etching the substrate surface is performed using an acid.

71. The method of claim 69, wherein etching the surface of the substrate is performed by heating the substrate in the presence of hydrogen.

72. The method of any one of claims 63 to 71, comprising removing contamination from the first surface of the lithium foil to expose lithium.

73. The method of any one of claims 63 to 72, wherein the lithium foil comprises about 92 weight percent (wt.%) to about 98 wt.% Li 7 isotope.

74. The method of any one of claims 63 to 73, wherein the lithium foil has a thickness of about 15 micrometers (μm) to about 180 μm.

75. The method of any one of claims 63 to 74, wherein the thermal conductivity of the substrate is about 300 W x m -1 ×K -1 About 1000W×m -1 ×K -1 .

76. The method of any one of claims 63 to 75, wherein the substrate comprises copper.

77. A method according to any one of claims 63 to 75, wherein the substrate comprises diamond.

78. The method of any one of claims 63 to 75, wherein the substrate comprises a copper-diamond powder composite material.

79. The method of any one of claims 63 to 78, wherein the thickness of the substrate is about 50 times, about 60 times, about 70 times, about 80 times, about 90 times, or about 100 times the thickness of the lithium foil.

80. The method of any one of claims 63 to 79, wherein the mechanical force is from about 1 MegaPascal (MPa) to about 3 MPa.

81. The method of claim 80, wherein the mechanical force is about 2 MPa.

82. The method of any one of claims 63 to 81, wherein applying lithium to the surface of the substrate to obtain the first lithium layer on the surface of the substrate comprises vapor depositing or plasma depositing lithium on the surface of the substrate.

83. The method of claim 82, wherein the vapor deposition or the plasma deposition is performed at atmospheric pressure.

84. The method of claim 82, wherein the vapor deposition or the plasma deposition is performed under vacuum.

85. The method of any one of claims 63 to 84, wherein the first layer has a thickness of about 0.01 μm to about 0.3 μm.

86. The method of claim 85, wherein the first layer has a thickness of about 0.1 μm.

87. The method of claim 1 or 2, wherein the first surface of the lithium foil contacts the surface of the substrate such that 99% or more of the macroscopic area of ​​the first surface of the lithium foil contacts a corresponding amount of area of ​​the surface of the substrate.

88. The method of claim 18 or 19, wherein the first surface of the lithium foil contacts the first layer such that 99% or more of a macroscopic area of ​​the first surface of the lithium foil contacts a corresponding amount of area of ​​the first layer.

89. The combination of claim 47 or 48, wherein 99% or more of the macroscopic area of ​​the first surface of the lithium foil is in contact with a corresponding amount of area of ​​the surface of the substrate.

90. The method of claim 63 or 64, wherein the first surface of the lithium foil is contacted with the first lithium layer in step (i) such that 99% or more of the macroscopic area of ​​the first surface of the lithium foil is in contact with the first lithium layer.

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