WO2022067003A1 - Apparatus and methods for treating disease or disorder - Google Patents

Abstract

Described herein is an apparatus for delivering a therapeutic agent to a site of a disease or disorder. The apparatus includes a reservoir configured to store a therapeutic agent, a hollow thread having a delivery channel and an opening, and a pump configured to drive a flow of the therapeutic agent from the reservoir into the delivery channel and exit through the opening. Also described herein is a method of treating, ameliorating, and/or preventing a disease or disorder using the apparatus.

Description

APPARATUS AND METHODS FOR TREATING DISEASE OR DISORDER

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No. 63/198,062, filed September 25, 2020, which is incorporated herein by reference in its entirety.

BACKGROUND

[0002] Treatments of many types of brain diseases face the obstacle of the blood-brain- barrier (BBB), which is a natural barrier that beneficially protects the brain from toxins and pathogens but unfortunately also blocks the exposure of the brain to systemically delivered drugs. For example, glioblastoma (GBM) is an aggressive deadly brain tumor. Despite all the technical advances, the standard of care for GBM has not changed in 15 years and the outcome remains poor, mainly because it is extremely difficult to deliver therapeutically effective antitumor medication across the BBB to the site of GBM within the brain.

[0003] Therefore, there is a need to develop apparatuses and methods for delivering therapeutic agent directly to the site of brain diseases or disorders and bypassing the BBB, such as directly to tumor cells. The instant specification addresses this need.

SUMMARY

[0004] In some embodiments, the instant specification is directed to, but not limited to, the following embodiments:

[0005] Embodiment 1, an apparatus comprising: at least one thread element comprising: a hollow thread, which comprises a delivery channel longitudinally within, and a hollow thread opening, wherein the hollow thread is in fluidic communication with the hollow thread opening, and wherein the thread element is configured to be inserted into a subject's body to guide delivery and release of a therapeutic agent into the subject's body; and a reservoir element, which is in fluidic communication with the delivery channel of the hollow thread, the reservoir element comprising: a reservoir configured to store the therapeutic agent; and a pump configured to drive flow of the therapeutic agent from the reservoir into and through the delivery channel and through the hollow thread opening.

[0006] Embodiment 2, the apparatus of embodiment 1, wherein the at least one thread element further comprises a valve located at the hollow thread opening, wherein the valve is configured to control, allow, and/or block flow of the therapeutic agent through the hollow thread opening.

[0007] Embodiment 3, the apparatus of embodiment 2, wherein the valve comprises a gate controllable by an external factor, and wherein the external factor comprises heat, radiation, sound, or combinations thereof.

[0008] Embodiment 4, the apparatus of any of embodiments 2-3, which further comprises a processor configured to control opening and/or closing of the valve

[0009] Embodiment 5, the apparatus of claim 4, which further comprises a first wiring electrically connecting the processor and the valve.

[00010] Embodiment 6, the apparatus of any of embodiments 1-6, further comprises: a transducer configured to detect, send, and/or receive a physical, biophysical, and/or biochemical signal.

[00011] Embodiment 7, the apparatus of any of embodiments 1-6, wherein the diameter of the at least one thread element is about 100 pm or less.

[00012] Embodiment 8, the apparatus of any of embodiments 1-7, wherein the apparatus comprises a plurality of thread elements.

[00013] Embodiment 9, the apparatus of any of embodiments 1-8, wherein the apparatus comprises between about 10 and about 500 independently selected thread elements.

[00014] Embodiment 10, the apparatus of any of embodiments 1-9, wherein the hollow thread of each at least one thread element has an independently selected plurality of openings, each of which is gated by an independently selected valve.

[00015] Embodiment 11, the apparatus of any of embodiments 1-10, wherein at least one hollow thread element has between about 5 and about 100 independently selected hollow thread openings.

[00016] Embodiment 12, the apparatus of any of embodiments 1-11, which further comprises the therapeutic agent within the reservoir.

[00017] Embodiment 13, a method of treating, ameliorating, and/or preventing a disease or disorder in a subject using the apparatus of any of embodiments 1-12, the method comprising: implanting the at least one thread elements in a subject's body that at least one hollow thread opening is in proximity to a site of the disease or disorder; opening at least one valve regulating flow across the at least one hollow thread opening in proximity to the site of the disease or disorder; and effecting delivery of the therapeutic agent stored in the reservoir through the at least one hollow thread opening in proximity to the site of the disease or disorder, wherein the therapeutic agent is effective in treating, ameliorating, and/or preventing the disease or disorder when in contact with the site of disease or disorder.

[00018] Embodiment 14, the method of embodiment 13, wherein the subject is a mammal.

[00019] Embodiment 15, the method of any of embodiments 13-14, wherein the subject is a human.

[00020] Embodiment 16, the method of any of embodiments 13-15, wherein the disease or disorder is a tumor and wherein the therapeutic agent comprises an anti-tumor medication.

[00021] Embodiment 17, the method of any of embodiments 13-16, wherein the disease or disorder is a brain tumor.

[00022] Embodiment 18, the method of any of embodiments 13-17, wherein the disease or disorder is a glioma, and wherein the therapeutic agent comprises temozolomide (TMZ), lomustine, carmustine, bevacizumab (B VZ), salts thereof, or combinations thereof.

[00023] Embodiment 19, the method of any of embodiments 13-18, further comprises determining the site of the disease or disorder with a medical imaging method.

[00024] Embodiment 20, the method of embodiment 19, wherein the site of disease or disorder comprises a brain tumor, and the wherein the medical imaging method comprises magnetic resonance imaging (MRI) or computed tomography (CT) scanning.

BRIEF DESCRIPTION OF THE DRAWINGS

[00025] The following detailed description of exemplary embodiments will be better understood when read in conjunction with the appended drawings. For the purpose of illustrating, non-limiting embodiments are shown in the drawings. It should be understood, however, that the instant specification is not limited to the precise arrangements and instrumentalities of the embodiments shown in the drawings.

[00026] Fig. 1 is an exemplary apparatus for treating brain disease or disorder in accordance with some embodiments. [00027] Fig. 2 is an exemplary apparatus for treating brain disease or disorder in accordance with some embodiments.

DETAILED DESCRIPTION

[00028] The following disclosure provides many different embodiments, or examples, for implementing different features of the provided subject matter. Specific examples of components and arrangements are described below to simplify the present disclosure. These are, of course, merely examples and are not intended to be limiting. For example, the formation of a first feature over or on a second feature in the description that follows may include embodiments in which the first and second features are formed in direct contact, and may also include embodiments in which additional features may be formed between the first and second features, such that the first and second features may not be in direct contact. In addition, the present disclosure may repeat reference numerals and/or letters in the various examples. This repetition is for the purpose of simplicity and clarity and does not in itself dictate a relationship between the various embodiments and/or configurations discussed.

Definitions

[00029] As used herein, each of the following terms has the meaning associated with it in this section. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Generally, the nomenclature used herein and the laboratory procedures in animal pharmacology, pharmaceutical science, peptide chemistry, and organic chemistry are those well-known and commonly employed in the art. It should be understood that the order of steps or order for performing certain actions is immaterial, so long as the present teachings remain operable. Any use of section headings is intended to aid reading of the document and is not to be interpreted as limiting; information that is relevant to a section heading may occur within or outside of that particular section. All publications, patents, and patent documents referred to in this document are incorporated by reference herein in their entirety, as though individually incorporated by reference.

[00030] In the application, where an element or component is said to be included in and/or selected from a list of recited elements or components, it should be understood that the element or component can be any one of the recited elements or components and can be selected from a group consisting of two or more of the recited elements or components.

[00031] In the methods described herein, the acts can be carried out in any order, except when a temporal or operational sequence is explicitly recited. Furthermore, specified acts can be carried out concurrently unless explicit claim language recites that they be carried out separately. For example, a claimed act of doing X and a claimed act of doing Y can be conducted simultaneously within a single operation, and the resulting process will fall within the literal scope of the claimed process.

[00032] In this document, the terms "a," "an," or "the" are used to include one or more than one unless the context clearly dictates otherwise. The term "or" is used to refer to a nonexclusive "or" unless otherwise indicated. The statement "at least one of A and B" or "at least one of A or B" has the same meaning as "A, B, or A and B."

[00033] " About" as used herein when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of ±20% or ±10%, in certain embodiments ±5%, in certain embodiments ±1%, in certain embodiments ±0.1% from the specified value, as such variations are appropriate to perform the disclosed methods.

[00034] A "disease" is a state of health of an animal wherein the animal cannot maintain homeostasis, and wherein if the disease is not ameliorated then the animal's health continues to deteriorate.

[00035] A "disorder" in an animal is a state of health in which the animal is able to maintain homeostasis, but in which the animal's state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the animal's state of health.

[00036] A disease or disorder is "alleviated" if the severity of a symptom of the disease or disorder, the frequency with which such a symptom is experienced by a patient, or both, is reduced.

[00037] As used herein, the terms "subject" and "individual" and "patient" can be used interchangeably and may refer to a human or non-human mammal or a bird. Non-human mammals include, for example, livestock and pets, such as ovine, bovine, porcine, canine, feline and murine mammals. In certain embodiments, the subject is human.

[00038] As used herein, the term "treatment" or "treating" is defined as the application or administration of a therapeutic agent, /.< ., a compound useful within the disclosure (alone or in combination with another pharmaceutical agent), to a patient, or application or administration of a therapeutic agent to an isolated tissue or cell line from a patient (e.g., for diagnosis or ex vivo applications), who has a disease or disorder and/or a symptom of a disease or disorder, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect the disease or disorder and/or the symptoms of the disease or disorder. Such treatments may be specifically tailored or modified, based on knowledge obtained from the field of pharmacogenomics.

Apparatus for Treating, Ameliorating, and/or Preventing a Disease or Disorder

[00039] In one aspect, the instant specification is directed to an apparatus. In some embodiments, the apparatus is an apparatus for treating, ameliorating, and/or preventing a disease or disorder, such as a brain disease or disorder, such as a brain tumor or a neurodegenerative disease or disorder in a brain. In some embodiments, the apparatus is configured to deliver a therapeutic agent in a controlled and precise manner directly to a location in proximity to a site of the disease or disorder, or otherwise treating the disease or disorder by acting in proximity to a site of the disease or disorder.

[00040] It is noteworthy that, although the instant specification uses mainly brain tumor, such as gliomas and glioblastomas as examples to illustrate the working mechanism of the apparatus, the instant invention is not limited thereto. One of ordinary skill in the art would understand that, although the ability of the apparatus described herein to deliver therapeutic agents bypass the blood-brain barrier makes the apparatus particularly relevant to treating brain disease or disorders such as brain tumors, the apparatus is suitable for delivering therapeutic agents to any part of a body of a subject.

[00041] Referring to Fig. 1, apparatus 100 includes a thread element 110 configured to be inserted into a body of a subject to guide delivery and release of a therapeutic agent, and a reservoir element 150 configured to store the therapeutic agent and drive the flow of the therapeutic agent. In some embodiments, the therapeutic agent is not considered part of the apparatus 100. In some embodiments, the apparatus 100 further includes the therapeutic agent. [00042] In some embodiments, the thread element 110 is packaged in to a master thread having a diameter of 100 pm or less, such as about 90 pm, such as about 80 pm, such as about 70 pm, such as about 60 pm, such as about 50 pm, such as about 40 pm, such as about 30 pm, such as about 25 pm, such as about 20 pm, such as about 15 pm, such as about 10 pm, such as about 5 pm.

[00043] Since the thread element 110 is configured to be inserted into the body of the subject, the geometric configuration, size, shape, and flexibility thereof are preferably configured to improve biocompatibility. In some embodiments, the thread element 110 or an exposed element of the thread element 110 is made from a biocompatible material. The desirable geometric configuration, size, shape, flexibility and material suitable for the thread element 110 are known in the art and detailed in, for example, the US patent publication US 2020/0085375 Al, the entirety of which is hereby incorporated herein by reference. In some embodiments, the dielectric elements of the thread element 110 includes a biocompatible polymer, such as but not limited to polyimide, epoxy, polyparaxylylene, parylene, acrylic, or combinations thereof. In some embodiments, the conductive elements of the thread element

110 includes gold or another metal.

[00044] Referring to Fig. 1, in some embodiments, the reservoir element 150 includes a reservoir 151, and the thread element 110 includes a hollow thread 111 having a delivery channel 115 an opening 113, and a pump 153.

[00045] In some embodiments, the reservoir 151 is configured to store the therapeutic agent. In some embodiments, the reservoir 151 is made from a biocompatible material, such as but not limited to a biocompatible polymer.

[00046] In some embodiments, the reservoir element 150 is configured to be fixed on a skull of the subject underneath the skin. In some embodiments, the reservoir element 150 is exposed to allow the replacement or replenishment of the therapeutic agent. In some embodiments, the reservoir element 150 has a shape the same as or similar to a hearing aid such that the reservoir element 150 can be worn behind an ear of the subject.

[00047] In some embodiments, the hollow thread I l l is configured to guide a flow of the therapeutic agent stored in the reservoir 151 via the delivery channel 115 and release the therapeutic agent via the opening 113.

[00048] In some embodiments, the hollow thread I l l is configured to be inserted into the brain of a subject. In some embodiments, the hollow thread 111 is configured to be inserted into the brain of the subject across the skull, thereby bypassing the blood-brain barrier. The manner by which the hollow thread 111 is inserted into the brain is detailed elsewhere herein. In some embodiments, the outer diameter of the hollow thread 111 ranges from 10 pm to 50 pm. In some embodiments, the hollow thread 111 is a flexible micro-thread. In some embodiments, the hollow thread I l l is made from a biocompatible material, such as but not limited to a biocompatible polymer-based material. In some embodiments, the hollow thread

111 is a graphene-based hollow thread (microtube).

[00049] In some embodiments, the pump 153 is configured to drive flow of the therapeutic agent from the reservoir 151 into and through the delivery channel 115 of the hollow thread 111, and exit from the opening 113.

[00050] In some embodiments, the thread element 110 further includes a valve 117 located at the opening 113 of the hollow thread 111, configured to control, allow, and/or block flow of the therapeutic agent across the opening 113. In some embodiments, the valve 117 is an electric bias-controlled valve. In some embodiments, the valve 117 is a spin-type and/or a micro-Janus particle-based valve. In some embodiments the valve 117 is driven by an induced-charge electrokinetic flow. In some embodiments, the valve 117 includes a gate controllable by an external factor, such as heat, radiation, or sound, for local release of the therapeutic agents. In some embodiments, the external factor is directed to the valve under stereotactic image guidance. In some embodiments, the valve 117 is an amorphous silicon- based detector capable of detecting a certain range of radiation dose and trigger a drugreleasing action in response.

[00051] In some embodiments, the apparatus 100 further includes a processor 155 that controls an opening and closing action of the valve 117. In some embodiments, the apparatus 100 further includes a first wiring element connecting the processor 155 and the valve 117 that transmits an instruction and/or power from the processor 155 to the valve 117. In some embodiments, the processor 155 is an application specific integrated circuit (ASIC) chip. In some embodiments, the ASIC chip is configured to be wirelessly controlled by a computer.

[00052] In some embodiments, the valve 117 and the first wiring 119 (or at least an element of the first wiring 119) are configured to be inserted into the brain of the subject together with the hollow thread 111. Therefore, in some embodiments, the hollow thread 111, the valve 117 and the first wiring 119 are packaged together into a master thread. In some embodiments, the valve 117 and the first wiring 119, or at least an insulating layer of the first wiring 119, are made from a biocompatible material.

[00053] In some embodiments, apparatus 100 further includes a second wiring 157 connecting the processor 155 and the pump 153. According to these embodiments, the processor 155 is further configured to control an output pressure of the pump 153. In some embodiments, the pump 153 is configured to provide a constant output pressure.

[00054] In some embodiments, the apparatus 100 further includes a transducer 121. In some embodiments, the apparatus 100 further includes a third wiring 123 that connects the processor 155 and the transducer 121. In some embodiments, the transducer 121 is configured to detect, send and/or receive a physical, biophysical or biochemical signal. In some embodiments, the transducer 121 is configured to emit an electromagnetic (EM) wave, such as an EM wave cytotoxic to tumor cells, or an immune stimulatory signal capable of inducing an anti-tumor immunity. In some embodiments, the transducer 121 is a sensor configured to monitor a treatment response by analyzing a tumor-specific electric signal or biochemical signal.

[00055] In some embodiments, the transducer 121 and the valve 117 are included in the same structure, such as but not limited to being integrated into one unit. For example, in some embodiments, the transducer 121 and the valve 117 are the same micro-transducer having a gating feature.

[00056] In some embodiments, the apparatus 100 includes a plurality of the thread element

110, such as between about 10 and about 500, such as about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 120, about 140, about 160, about 180, about 200, about 150, about 200, about 250, about 300, about 400, or about 500 hollow threads 111. In some embodiments, each thread element 110 of the plurality of thread elements comprises one hollow thread.

[00057] In some embodiments, the apparatus 100 includes a plurality of the hollow thread

111, such as between about 10 and about 500, such as about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 120, about 140, about 160, about 180, about 200, about 150, about 200, about 250, about 300, about 400, or about 500 hollow threads 111.

[00058] In some embodiments, the hollow thread 111 has a plurality of openings 113, each is controlled by a valve 117. In some embodiments, each hollow thread 111 has about 5 to about 100 openings, such about 5, about 10, about 15, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, or about 100 openings 113.

[00059] Referring to Fig. 2, in some embodiments, the apparatus 200 including a reservoir element 250/250’ and a plurality of thread elements 210 is implanted in the subject such that the reservoir element 250/250’, which includes the reservoir and the control processor, is at least partially exposed, and the thread elements 210 are implanted in different directions and the openings, the valves 217/217’, and the transducers 221/221’ are distributed in different regions in the brain. According to these embodiments, since the paths of thread elements 210 are known before, during, or after the implantation process, and the locations of each opening, valve 217/217’, and transducer 221/221’ in relative to the thread elements 210 are known as well, the locations of each of the openings and valves 217/217’ in the brain of the subject are known. In addition, the precise location of the disease or disorder can be determined by conventional methods such as magnetic resonance imaging (MRI) and/or computed tomography (CT) scanning. As such, the valves 217/217’ and the transducers 221/221’ can be controlled such that only the valves 217’ near a site of disease or disorder are opened and the therapeutic agent is released only near the site of disease or disorder, or that only the transducer 221’ near a site of the disease or disorder is emitting EM wave cytotoxic to tumor cells or immune stimulatory signals to induce anti-tumor immunity. The control of the valves 217/217’ is, depending the types of the valves 217/217’, by the processor or triggered externally by signals such as radiation, sound, and other elements known in the art. In some embodiments, the processor is programed to control the valves 217/217’, and the processor is further programed to control the output pressure of the pump based on, for example, a number of valves 217’ that are being opened, a resistance to the flow of the therapeutic agent to the openings, and so forth, such that a quantity of the therapeutic agent that are being released is precisely controlled.

[00060] Also shown in Fig. 2, in some embodiments, the reservoir element can be made as a two-piece design: a first reservoir element 250 permanently connected to the thread element 210, and a second reservoir element 250’ detachable from the first reservoir element 250. In some embodiments, the first reservoir element 250 is an implantable interfacing unit configured to be implanted into the body of the subject and having an element thereof exposed to receive the detachable second reservoir element 250’. In some embodiments, the reservoir, the processor and/or the pump can be configured as part of the second reservoir element 250’ such that these structures can be replaced or reconfigured.

[00061] In some embodiments, the implanted elements of the apparatus 100 are removable. In some embodiments, the implanted elements of the apparatus 100 are configured such that these elements can remain in the brain for, e.g., long-term monitoring or further therapeutic intervention.

[00062] The equipment and methods for implanting the instant apparatus are known in the art and are detailed in, for example, US patent publications US2020/0086111A1 and US2020/0085508 Al, the entireties of which are hereby incorporated herein by reference.

Method of Treating, Ameliorating, and/or Preventing Disease or Disorder

[00063] In one aspect, the instant specification is directed to a method of treating, ameliorating, and/or preventing a disease or disorder in a subject.

[00064] In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

[00065] In some embodiment, the method includes implanting an apparatus the same as or similar to that described above in the “Apparatus for Treating Disease or disorder” section such that at least one thread element, opening/valve, and/or transducer is located in proximity to a site of disease or disorder, and deliver a therapeutic agent or emitting EM wave cytotoxic/immune stimulatory signal to the site of disease or disorder in the subject.

[00066] In some embodiments, the apparatus being used includes a plurality of thread elements, each of which has a plurality of openings regulated by a valve. According to these embodiments, the method includes implanting the at least one thread element in the body of the subject such that one or more openings of at least one hollow thread is in proximity to a site of the disease or disorder; opening one or more valve regulating a flow across the one or more openings; and pumping the therapeutic agent stored in the reservoir such that the therapeutic agent is released from the one or more openings of the at least one hollow thread, wherein the therapeutic agent is effective in treating the disease or disorder when in contact with the site of disease or disorder.

[00067] In some embodiments, the method further includes performing a medical imaging on the subject to locate the site of disease or disorder.

[00068] In some embodiments, the site of disease or disorder includes a tumor. Accordingly, in some embodiments, the therapeutic agent includes an anti-tumor agent such as a chemotherapeutic agent.

[00069] Glioblastoma or GBM is an aggressive tumor that accounts for 48 percent of all primary malignant brain tumors. It is estimated that more than 10,000 individuals in the United States will succumb to glioblastoma every year. The five-year survival rate for glioblastoma patients is only 6.8 percent, and the average length of survival for glioblastoma patients is estimated to be only 12 to 18 months. Survival rates and mortality statistics for GBM have been virtually unchanged for decades. Despite first being identified in the scientific literature in the 1920’s, and the enormous public and private investments into basic, translational, and clinical research, there have only been four drugs and one device ever approved by the FDA for the treatment of glioblastoma. The standard of care (i.e., maximal surgical resection followed by adjuvant radiation and temozolomide chemotherapy) has not changed in 15 years, and yields a median survival of about 15 months and a 5-year survival of less than 5%.

[00070] Distinct pathophysiologic challenges at least partially explain the lack of progress in GBM therapies. First, GBM is a locally infiltrative brain malignancy without a well-defined border; surgical resection cannot be extended to obtain a tumor free margin. Therefore, adjuvant chemotherapy and radiation therapy (RT) are required after surgery, and the clinical efficacy of these two modalities is so far limited. Second, chemotherapy for brain tumors must cross the blood-brain-barrier (BBB) to have a therapeutic effect; poor BBB penetration can lead to limited anticancer activity despite systemic toxi cities. Third, in the setting of RT, the dose is limited by RT tolerance of the normal brain parenchyma. Fourth, the efficacy of other therapies, including targeted agents and immunotherapy, is impeded by GBM's intratumoral genetic heterogeneity and its immunosuppressive tumor microenvironment, which is marked by scant effector T-cell infiltration, preventing the antitumor efficacy of immune checkpoint inhibitors. Finally, radiation treatment is known to up-regulate notch signaling and lead to new phenotypes of tumor cells that subsequently contribute to the development of tolerance to drugs.

[00071] The apparatus described in the instant specification is particularly useful for treating, ameliorating, and/or preventing malignant gliomas such as glioblastoma, at least because the implanted hollow thread can transport therapeutic agents across the blood-brain barrier, and the openings and the valves allow the therapeutic agent(s) to be released in a precise and controlled manner directly at the sites of glioblastoma.

[00072] Therefore, in some embodiments, the site of disease or disorder includes a glioma in the brain of the subject. In some embodiments, the site of disease or disorder includes a glioblastoma in the brain of the subject. In some embodiments, the therapeutic agent includes a medication for glioma, such as for glioblastoma. In some embodiments, the therapeutic agent includes temozolomide (TMZ), lomustine, carmustine, bevacizumab (BVZ), salts thereof, or combinations thereof. Therapeutic agents for gliomas, such as glioblastomas are known in the art, and are detailed in, for example, Fisher et al., Biomedicines, Mar 22;9(3):324 (2021), the entirety of which is hereby incorporated by reference.

[00073] In some embodiments, the method includes performing magnetic resonance imaging (MRI) or computed tomography (CT) scanning to locate the glioma, such as glioblastoma, in the brain of the subject. In some embodiments, the method further includes selecting at least one opening of the implanted hollow thread located in proximity to the glioma, such as glioblastoma.

[00074] The foregoing outlines features of several embodiments so that those skilled in the art may better understand the aspects of the present disclosure. Those skilled in the art should appreciate that they may readily use the present disclosure as a basis for designing or modifying other processes and structures for carrying out the same purposes and/or achieving the same advantages of the embodiments introduced herein. Those skilled in the art should also realize that such equivalent constructions do not depart from the spirit and scope of the present disclosure, and that they may make various changes, substitutions, and alterations herein without departing from the spirit and scope of the present disclosure.

Claims

CLAIMS What is claimed:

1. An apparatus comprising: at least one thread element comprising: a hollow thread, which comprises a delivery channel longitudinally within, and a hollow thread opening, wherein the hollow thread is in fluidic communication with the hollow thread opening, and wherein the thread element is configured to be inserted into a subject's body to guide delivery and release of a therapeutic agent into the subject's body; and a reservoir element, which is in fluidic communication with the delivery channel of the hollow thread, the reservoir element comprising: a reservoir configured to store the therapeutic agent; and a pump configured to drive flow of the therapeutic agent from the reservoir into and through the delivery channel and through the hollow thread opening.

2. The apparatus of claim 1, wherein the at least one thread element further comprises a valve located at the hollow thread opening, wherein the valve is configured to control, allow, and/or block flow of the therapeutic agent through the hollow thread opening.

3. The apparatus of claim 2, wherein the valve comprises a gate controllable by an external factor, and wherein the external factor comprises heat, radiation, sound, or combinations thereof.

4. The apparatus of any of claims 2-3, which further comprises a processor configured to control opening and/or closing of the valve.

5. The apparatus of claim 4, which further comprises a first wiring electrically connecting the processor and the valve.

6. The apparatus of any of claims 1-5, which further comprises: a transducer configured to detect, send, and/or receive a physical, biophysical, and/or biochemical signal.

7. The apparatus of any of claims 1-6, wherein the diameter of the at least one thread element is about 100 pm or less.

8. The apparatus of any of claims 1-7, wherein the apparatus comprises a plurality of thread elements.

9. The apparatus of any of claims 1-8, wherein the apparatus comprises between about 10 and about 500 independently selected thread elements.

10. The apparatus of any of claims 1-9, wherein the hollow thread of each at least one thread element has an independently selected plurality of openings, each of which is gated by an independently selected valve.

11. The apparatus of any of claims 1-10, wherein at least one hollow thread element has between about 5 and about 100 independently selected hollow thread openings.

12. The apparatus of any of claims 1-11, which further comprises the therapeutic agent within the reservoir.

13. A method of treating, ameliorating, and/or preventing a disease or disorder in a subject using the apparatus of any of claims 1-12, the method comprising: implanting the at least one thread elements in a subject's body that at least one hollow thread opening is in proximity to a site of the disease or disorder; opening at least one valve regulating flow across the at least one hollow thread opening in proximity to the site of the disease or disorder; and effecting delivery of the therapeutic agent stored in the reservoir through the at least one hollow thread opening in proximity to the site of the disease or disorder, wherein the therapeutic agent is effective in treating, ameliorating, and/or preventing the disease or disorder when in contact with the site of disease or disorder.

14. The method of claim 13, wherein the subject is a mammal.

15. The method of any of claims 13-14, wherein the subject is a human.

16. The method of any of claims 13-15, wherein the disease or disorder is a tumor and wherein the therapeutic agent comprises an anti-tumor medication.

17. The method of any of claims 13-16, wherein the disease or disorder is a brain tumor.

18. The method of any of claims 13-17, wherein the disease or disorder is a glioma, and wherein the therapeutic agent comprises temozolomide (TMZ), lomustine, carmustine, bevacizumab (BVZ), salts thereof, or combinations thereof.

19. The method of any of claims 13-18, further comprising determining the site of the disease or disorder using a medical imaging method.

20. The method of claim 19, wherein the site of disease or disorder comprises a brain tumor, and the wherein the medical imaging method comprises magnetic resonance imaging (MRI) or computed tomography (CT) scanning.

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