CROSS-REFERENCE TO RELATED APPLICATIONS

[001] This application claims priority to U.S. Provisional Patent Application Ser. No. 63/132,632, filed December 31 , 2020, the entirety of which is incorporated herein by reference.

BACKGROUND

[002] Challenges surrounding the blood-brain barrier and common neurological diseases, like malignant brain tumors for example, have remained daunting to neurosurgeons and neuro-oncologists alike (Vogelbaum et al., “Convection-enhanced delivery for the treatment of glioblastoma,” Neuro Oncol., 17(2):3-8 (2015)). In parallel with these challenges, optimization of cranial implant size and dimension is needed to ensure optimal reconstruction with absent visual deformity and biocompatible placement to avoid impinging the scalp from underneath or the brain from above, which assures safer outcomes for patients in need of cranial implant or cranioplasty reconstruction. Recent innovations in implant design, mainly those that emolliate the issue of temporal hollowing following wasting of the temporalis muscle and temporal fat pad, have made great strides by adding additional thickness to the standard size pterional cranial implant (Zhong et al., “Quantitative analysis of dual-purpose, patient-specific craniofacial implants for correction of temporal deformity,” Neurosurgery, 11 :220-229 (2015) and U.S. Patent Application Publication No. US 2019/0021863) which in turn, provides room for embedded technologies.

[003] Accordingly, there remains a need for additional implant devices and related fluidic materials conveyance methods.

SUMMARY

[004] This application discloses magnetic resonance imaging (MRI) compatible, cranial implant devices, electroosmotic (EO) pumps, and related methods for performing a wide array of therapeutic and/or monitoring applications. Once implanted in subjects, the devices may remain in place for indefinite durations with minimal risk of infection, since they can be refilled using a percutaneous needle. The devices have substantially anatomically-compatible shapes such that they are essentially non-detectable upon implantation in subjects, whereby they employ the skull space to avoid scalp or brain impingement. In addition to selectively administering therapeutic agents to subjects, the devices may also include an embedded imaging devices capable of providing image data to healthcare providers to monitor efficacy of treatment and/or need for repeat surgery. In some embodiments, the implants disclosed herein are used to replace missing skull segments, for example, from a previous surgical procedure, whereas in other exemplary embodiments, the implants are used intraoperatively following the removal of a skull bone flap.

[005] In one aspect, this disclosure provides an electroosmotic (EO) pump comprising an internal element comprising an active EO element disposed at least partially within a first housing that comprises at least two openings. A first bellow structure is operably connected to the first housing and communicates with a first opening of the at least two openings. A second bellow structure is operably connected to the first housing and communicates with a second opening of the at least two openings, which active EO element is configured to convey at least a first fluidic material at least between the first and second bellow structures to effect movement of the first and second bellow structures when the internal element comprises the first fluidic material. In addition, the EO pump also includes an external element comprising a second housing that comprises at least two orifices. The internal element is at least partially disposed within the second housing such that when the first fluidic material is conveyed at least between the first and second bellow structures of the internal element and at least a first orifice of the second housing communicates with a source of at least a second fluidic material, the second fluidic material is conveyed through the first orifice and the second housing and out of at least a second orifice of the second housing. In some embodiments, the EO pump further comprises at least one sensor element at least within sensory communication of the internal element and/or the external element, which sensor element is configured to sense a position of one or more components of the EO pump. [006] In another aspect, this disclosure provides a cranial implant device that includes at least one cranial implant housing configured for intercranial implantation in at least one cranial opening of a subject. The cranial implant device also includes at least two functional components at least partially disposed within the cranial implant housing. A first functional component comprises a fluid-based physiological condition intervention system that comprises at least one electroosmotic (EO) pump configured to convey at least one fluidic therapeutic agent from the first functional component to the subject through at least one fluid conduit. A second functional component comprises a non-fluid-based physiological condition intervention system configured to transmit one or more therapeutic signals from the second functional component to the subject through at least one non-fluid conduit. In addition, the cranial implant device also includes at least one power source at least partially disposed within the cranial implant housing, which power source is operably connected to the functional components.

[007] In some embodiments, the cranial implant housing, the functional components, and/or the power source are fabricated from one or more magnetic resonance imaging (MRI) compatible materials. In some embodiments, the cranial implant housing, the functional components, and/or the power source comprises one or more of titanium mesh, porous hydroxyapatite (HA), polymethylmethacrylate (PMMA), polyether ether ketone (PEEK), porous polyethylene, cubic zirconia (CZ), or combinations thereof. In some embodiments, the cranial implant housing comprises a substantially anatomically-compatible shape. In some embodiments, the power source comprises at least one zero-volt battery.

[008] In some embodiments, the functional components are configured to deliver one or more therapies to the subject selected from the group consisting of antitumor, anti-seizure, anti-Parkinson, anti-Huntington, anti-hydrocephalus, anti-ADHD, anti-Alzheimer’s, anti-pain, anti-insomnia, anti-depression, anti-schizophrenia, antiaging, energy-enhancing, memory-enhancing, mind-enhancing, neuro-protective, and combinations thereof. In some embodiments, the therapeutic signals comprise an electrical signal, a magnetic signal, an optical signal, or combinations thereof. [009] In some embodiments, the cranial implant housing comprises at least first and second surfaces, and at least one fluidic circuit comprising at least one cavity and at least one port that fluidly communicates with the cavity through at least the second surface, wherein the cavity comprises, or is capable of comprising, the fluidic therapeutic agent. In some embodiments, the EO pump is operably connected to the fluidic circuit. In some embodiments, the cranial implant housing comprises at least one self-sealing access port disposed at least partially in or through the first surface, which self-sealing access port fluidly communicates with the cavity and is configured to receive one or more syringe needles through the scalp of the subject to add and/or remove the fluidic therapeutic agent to/from the cavity.

[010] In some embodiments, the cranial implant device comprises at least one controller at least partially disposed within the cranial implant housing, which controller is operably connected to the functional components and the power source, and is configured to selectively effect the EO pump of first functional component to convey the fluidic therapeutic agent through the fluid conduit to the subject and the second functional component to transmit the therapeutic signals through the non-fluid conduit to the subject. In some embodiments, the controller is configured for wireless connectivity so as to be remotely monitored, activated, and/or adjusted. In some embodiments, the first functional component comprises one or more detectors at least partially disposed within cranial implant housing and operably connected at least to the controller, which detectors are configured to detect information from the subject and/or the device, which information is selected from the group consisting of: a volume of fluidic therapeutic agent disposed in a cavity of the device, a volume of fluidic therapeutic agent conveyed through a fluidic circuit, a pressure of the fluidic therapeutic agent within the fluidic circuit and/or proximal thereto, a leakage of the fluidic therapeutic agent from the fluidic circuit, a status of the power source, a device component malfunction, and a detectable signal from the subject. In some embodiments, the fluid conduit and/or the non-fluid conduit extend from the cranial implant housing.

[011] In some embodiments, the fluid conduit and the non-fluid conduit are configured for fluidic, electrical, magnetic, and optical communication between the functional components and the subject. In some embodiments, the second functional component comprises at least one detector that is configured to detect information from the subject and/or the device. In some embodiments, the functional components are configured to provide acute neurological intervention comprising medicinal therapy, electro-stimulation therapy, radiation therapy, chemotherapy, or a combination thereof. In some embodiments, one or more of the functional components comprises a vital sign monitor, a brain function monitor, an ultrasound device, an optical coherence tomography (OCT) image monitor, a camera, an intracranial pressure (ICP) monitor, an electroencephalography sensor (ECOG), and/or a remote imaging monitor. In some embodiments, the second functional component is configured to provide neuron modulation via optic sensors. In some embodiments, the second functional component is configured for computerized monitoring of at least one physiological condition. In some embodiments, the second functional component is configured to monitor a diseased portion of brain parenchyma, a dead-space cavity following brain tumor resection, and/or a blood vessel, neuron or ventricle of a brain.

[012] In another aspect, this disclosure provides an implant device that includes at least one implant housing configured for implantation in at least one opening of a subject. The implant housing comprises a substantially anatomically-compatible shape, at least first and second surfaces, and at least one fluidic circuit comprising at least one cavity and at least one port that fluidly communicates with the cavity through at least the second surface. The cavity comprises, or is capable of comprising, at least one fluidic therapeutic agent. The implant device also includes at least one electroosmotic (EO) pump operably connected to the fluidic circuit, which EO pump is configured to convey the fluidic therapeutic agent from the cavity through at least one fluid conduit when the fluid conduit is operably connected to the port to maintain at least one positive pressure gradient of the fluidic therapeutic agent at least proximal to an outlet of the fluid conduit. The implant device also includes at least one controller operably connected at least to the EO pump, which controller is configured to selectively effect the EO pump to convey the fluidic therapeutic agent through the fluid conduit when the fluid conduit is operably connected to the port and the cavity comprises the fluidic therapeutic agent. The implant device also includes at least one power source operably connected at least to the controller. In addition, the implant housing, the EO pump, the controller, and the power source are fabricated from one or more magnetic resonance imaging (MRI) compatible materials.

[013] In another aspect, this disclosure provides a microfluidic device, comprising a body structure that comprises at least one channel that communicates with a least one chamber, wherein at least one cross-sectional dimension of the chamber is greater than at least one cross-sectional dimension of the channel such that when fluidic materials comprising particles are conveyed from the channel into the chamber, at least two different sized particles at least partially separate from one another in the chamber. In some embodiments, the microfluidic device further comprises an electroosmotic (EO) pump that communicates with the channel and/or the chamber.

[014] In another aspect, this disclosure provides a method of treating a neurologically-related disease, condition or disorder of a subject. The method comprises surgically implanting at least one cranial implant device in at least one cranial opening of the subject. The cranial implant device comprises at least one implant housing configured for implantation in the cranial opening of the subject, which implant housing comprises a substantially anatomically-compatible shape, at least first and second surfaces, and at least one fluidic circuit comprising at least one cavity and at least one port that fluidly communicates with the cavity through at least the second surface, wherein the cavity comprises, or is capable of comprising, at least one fluidic therapeutic agent. The cranial implant device comprises at least one electroosmotic (EO) pump operably connected to the fluidic circuit, which EO pump is configured to convey the fluidic therapeutic agent from the cavity through at least one fluid conduit when the fluid conduit is operably connected to the port to maintain at least one positive pressure gradient of the fluidic therapeutic agent at least proximal to an outlet of the fluid conduit. The cranial implant device comprises at least one controller operably connected at least to the EO pump, which controller is configured to selectively effect the EO pump to convey the fluidic therapeutic agent through the fluid conduit when the fluid conduit is operably connected to the port and the cavity comprises the fluidic therapeutic agent. The cranial implant device also comprises at least one power source operably connected at least to the controller. In addition, the implant housing, the EO pump, the controller, and the power source are fabricated from one or more magnetic resonance imaging (MRI) compatible materials. The method also includes conveying an effective amount of the fluidic therapeutic agent from the cavity through the fluid conduit to maintain the positive pressure gradient of the fluidic therapeutic agent at least proximal to the outlet of the fluid conduit within the cranial cavity of the subject, thereby treating the neurologically-related disease, condition or disorder of the subject.

BRIEF DESCRIPTION OF THE DRAWINGS

[015] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate certain embodiments, and together with the written description, serve to explain certain principles of the cranial implant devices, electroosmotic (EO) pumps, and related methods disclosed herein. The description provided herein is better understood when read in conjunction with the accompanying drawings which are included by way of example and not by way of limitation. It will be understood that like reference numerals identify like components throughout the drawings, unless the context indicates otherwise. It will also be understood that some or all of the figures may be schematic representations for purposes of illustration and do not necessarily depict the actual relative sizes or locations of the elements shown.

[016] Figures 1A-G schematically show aspects of a cranial implant device according to exemplary embodiments.

[017] Figures 2A-C schematically show aspects of a cranial implant device according to exemplary embodiments.

[018] Figures 3A-E schematically show electroosmotic pumps according to exemplary embodiments.

[019] Figures 4A-C schematically show aspects of a cranial implant system according to exemplary embodiments.

DEFINITIONS

[020] In order for the present disclosure to be more readily understood, certain terms are first defined below. Additional definitions for the following terms and other terms may be set forth through the specification. If a definition of a term set forth below is inconsistent with a definition in an application or patent that is incorporated by reference, the definition set forth in this application should be used to understand the meaning of the term.

[021] As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural references unless the context clearly dictates otherwise. Thus, for example, a reference to “a method” includes one or more methods, and/or steps of the type described herein and/or which will become apparent to those persons skilled in the art upon reading this disclosure and so forth.

[022] It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting. Further, unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. In describing and claiming the methods, cranial implant devices, and component parts, the following terminology, and grammatical variants thereof, will be used in accordance with the definitions set forth below.

[023] About: As used herein, “about” or “approximately” as applied to one or more values or elements of interest, refers to a value or element that is similar to a stated reference value or element. In certain embodiments, the term “about” or “approximately” refers to a range of values or elements that falls within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of the stated reference value or element unless otherwise stated or otherwise evident from the context (except where such number would exceed 100% of a possible value or element).

[024] Administer: As used herein, “administering” a composition or therapeutic agent to a subject means to give, apply or bring the composition into contact with the subject. Administration can be accomplished by any of a number of routes, including, for example, topical, oral, subcutaneous, intercranial, intramuscular, intraperitoneal, intravenous, intrathecal and intradermal.

[025] Customized: As used herein, “customized” in the context of cranial implant shapes refers to a shape that has been created at the point of fabrication specifically for an individual subject. In some embodiments, for example, custom craniofacial implants (CCIs) are designed and manufactured using computer-aided design/manufacturing (CAD/CAM) based in part on fine cut preoperative computed tomography (CT) scans and three-dimensional reconstruction (+/- stereolithographic models).

[026] Detect: As used herein, “detect,” “detecting,” or “detection” refers to an act of determining the existence or presence of one or more characteristics, properties, states, or conditions in a subject, in a sample obtained or derived from a subject, or in a device, system, or component thereof.

[027] Functional Component: As used herein, “functional component” means any therapeutic hardware or compositions including, but not limited to, medicines to treat any patient-specific illness, or electronic, mechanical, imaging modality and/or electro-mechanical device to remotely monitor (e.g., via Wi-Fi connectivity) or intervene any specific neurologic illness, including imaging, monitoring, electrostimulation, radiation therapy, polarized light/laser neuronal modulation devices.

[028] Sample: As used herein, “sample” means anything capable of being analyzed using a device or system disclosed herein. Exemplary sample types include environmental samples and biological samples.

[029] Standardized: As used herein, “standardized” in the context of cranial implant shapes refers to a shape that has not been created at the point of fabrication specifically for any individual subject. Instead, a standardized implant shape is typically selected for ease of readily reproducible manufacture. Cranial implants having standardized shapes may also be referred to as “off the shelf” neurological implants.

[030] Subject: As used herein, “subject” refers to an animal, such as a mammalian species (e.g., human) or avian (e.g., bird) species. More specifically, a subject can be a vertebrate, e.g., a mammal such as a mouse, a primate, a simian or a human. Animals include farm animals (e.g., production cattle, dairy cattle, poultry, horses, pigs, and the like), sport animals, and companion animals (e.g., pets or support animals). A subject can be a healthy individual, an individual that has or is suspected of having a disease or a predisposition to the disease, or an individual that is in need of therapy or suspected of needing therapy. The terms “individual” or “patient” are intended to be interchangeable with “subject.” For example, a subject can be an individual who has been diagnosed with having a cancer, is going to receive a cancer therapy, and/or has received at least one cancer therapy. The subject can be in remission of a cancer.

[031] Substantially Anatomically-Compatible Shape: As used herein, “substantially anatomically-compatible shape” in the context of cranial implant devices refers to a shape such that when the device is implanted in a subject, the device is essentially visually imperceptible in the absence of, for example, analytical imaging, such as X-ray-based imaging or the like.

[032] System: As used herein, "system" in the context of analytical instrumentation refers a group of objects and/or devices that form a network for performing a desired objective.

[033] Therapy: As used herein, “therapy” or “treatment” refers to the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder. This term includes active treatment, that is, treatment directed specifically toward the improvement of a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder. In addition, this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder. In various aspects, the term covers any treatment of a subject, including a mammal (e.g., a human), and includes: (i) preventing the disease from occurring in a subject that can be predisposed to the disease but has not yet been diagnosed as having it; (ii) inhibiting the disease, i.e., arresting its development; or (iii) relieving the disease, i.e., causing regression of the disease. In one aspect, the subject is a mammal such as a primate, and, in a further aspect, the subject is a human.

DETAILED DESCRIPTION

[034] This application discloses magnetic resonance imaging (MRI) compatible cranial implant devices and related methods for performing a wide array of therapeutic and/or monitoring applications. Once implanted in subjects, the devices may remain in place for indefinite durations. The devices have substantially anatomically-compatible shapes such that they are essentially visually non-detectable to the naked eye upon implantation in subjects and safely avoid pressure on the scalp above or brain below. The devices also include electroosmotic (EO) pumps to convey fluidic materials within and to and from the devices. In some embodiments, the present disclosure also provides inertial focusing elements, for example, as part of stand-alone microfluidic devises or integrated as part of an implant device. In addition to selectively administering therapeutic agents to subjects, the devices also typically include imaging devices that provide image data to patients, patient family/friends, healthcare providers to monitor courses of treatment. The implantable devices described herein typically include low-profiles (e.g., to avoid scalp-related complications and high extrusion risk leading to premature explantation). Optionally, the devices described herein are configured for implantation elsewhere in a patient’s body, such as in the thoracic cavity (e.g., to treat cardiovascular or pulmonary disease), the abdominal cavity (e.g., to treat hepatological disease), or the pelvic cavity (e.g., to treat ovarian, uterine or prostatic disease) for non-brain related pathologies and chronic illnesses. In these embodiments, the implant devices are also typically configured to be MRI compatible. Aspects related to implant devices and the conveyance of fluidic materials are also described in International Application No. PCT/US2019/039519, filed 27 June 2019, the entire disclosure of which is incorporated herein by reference.

[035] By way of overview, Figures 1A-G schematically show aspects of a cranial implant device according to exemplary embodiments. In particular, Figure 1A schematically shows the placement of implant device 100 in a cranial defect of subject 101. Figures 1 B-G schematically show aspects of implant device 100 in greater detail. As shown, implant device 100 includes implant housing 102 configured for implantation in an opening of subject 101. Implant housing 102 comprises a substantially anatomically-compatible shape, at least first and second surfaces (104 and 106, respectively), and fluidic circuit 108 comprising cavity 110 and port 112 (shown as a self-sealing septum) that fluidly communicates with cavity 110 through second surface 106. Cavity 110 comprises, or is capable of comprising, at least one fluidic therapeutic agent. Implant device 100 also includes electroosmotic (EO) pump 114 operably connected to fluidic circuit 108. EO pump 114 is configured to convey the fluidic therapeutic agent from cavity 110 through a fluid conduit when the fluid conduit is operably connected to port 112 to maintain at least one positive pressure gradient of the fluidic therapeutic agent at least proximal to an outlet of the fluid conduit (e.g., a catheter or the like). EO pumps are described further herein. Implant device 100 also includes a controller (not within view) operably connected at least to EO pump 114. The controller is configured to selectively effect EO pump 114 to convey the fluidic therapeutic agent through a fluid conduit when the fluid conduit is operably connected to port 112 and cavity 110 comprises the fluidic therapeutic agent. A power source (not within view) is also operably connected at least to the controller.

[036] In some embodiments, the design of the chip or implant device involves three subsystems: (1 ) the chip itself which focuses the sample (e.g., using inertial focusing), (2) the inlet and outlet system that enables the fluid to flow in and out of the chip, and (3) the sensing system that detects the presence of the target particle, such as a biomarker. In some of these embodiments, the chip itself has specific dimensions to create the inertial focusing phenomenon and a narrow inlet channel 130 (e.g., where CSF flows from the pump), which connects to the collection chamber 132 (e.g., a chamber for biomarker collection, such that biomarkers will migrate and vortex as the flow runs), which connects to the narrow outlet channel 134. The collection chamber is where the particles in the fluid separate by size. The fluid enters the inlet channel by flowing through the inlet tube 136 (e.g., a tube to carry CSF to the inlet area) via opening 137 and fluid exits the outlet channel 134 through the outlet tube 138. The other end of the outlet tube 138 returns the fluid to its original location, such as back into the patient’s CSF, or into a reservoir (such as a reservoir of a medicine delivery device described herein). In some embodiments, the fluid enters the inlet tube at a specific flow rate with an electroosmotic pump 141 , as described herein. In these embodiments, the sensing system 140 that detects the presence of the target particle, such as a biomarker, can be a physical sensor that detects the presence of biomarkers or fluorescence, or another tagging mechanism. For example, the sensing system can include a compartment, such as a reservoir, that contains fluorescent markers that are injected into the collection chamber 132. In some embodiments, sensor data is relayed to an external device via wireless connection 143.

[037] To further illustrate, Figures 2A-C schematically show aspects of another cranial implant device according to exemplary embodiments. As shown, implant device 200 includes housing or case 202, which includes reservoir or cavity 204 that fluidly communicates with catheters 206. Implant device 200 also includes battery 208 operably connected to wireless power transfer or charger 210, hardware 212, and pump 214. As also shown, implant device 200 also includes port 216 and fluid control bladder 218. In addition, implant device 200 also includes filter 220 operably connected to the fludic circuit in this exemplary embodiment.

[038] Typically, cranial implant devices (e.g., fabricated from MRI-compatible materials) are inserted in a resected or missing portion of a patient’s skull during a surgical procedure, such as a surgical implantation procedure for various forms of neuroplastic surgery, craniomaxillofacial surgery and/or neurosurgery including an implant-based cranioplasty according to one exemplary embodiment. To further illustrate, Figure 1A also schematically shows cranial implant device 100 being inserted into a resected portion of a removed or missing skull according to one exemplary embodiment. In certain exemplary embodiments, the cranial implant devices described herein are miniaturized and implanted within a patient’s own bone flap being replaced following a common neurosurgical craniotomy. In some of these embodiments, a given cranial implant device may be partly or fully recessed within the undersurface of one’s own bone flap following craniotomy and replaced accordingly. Cranial implant devices typically include a cranial implant housing, which includes a form or shape that is customized for the missing or resected portion of the skull. In some of these embodiments, for example, a given cranial implant device may be embedded within the skull space as either a universal or standard design or a patient-specific implant device using a customized design following computer-assisted design and modeling for patientspecific dimensions. In other embodiments, cranial implant housings are fabricated with standardized forms (e.g., an off the shelf modular design that may be universal or standard and embedded within a skull space as a stand-alone device), the shapes of which are optionally further modified prior to surgical implantation. In some embodiments, cranial implant devices also include functional components, which fluidly communicate with fluid conduits. Fluid conduits are typically of a selected length and disposed at an angle relative to a cranial implant housing such that an outlet of a fluid conduit is positioned at a desired location within the cranial cavity of the patient’s skull (e.g., a diseased portion of brain parenchyma, a dead-space cavity following brain tumor resection, and/or a blood vessel (e.g., a feeding blood vessel), neuron or ventricle of the brain). As described further herein, functional components typically include a fluid-based physiological condition intervention system that includes a convection- enhanced delivery (CED) and/or an EO pump configured to convey one or more fluidic therapeutic and/or diagnostic agents (e.g., an optogenetic protein, a stem cell, an immune cell, an antibody, an enzyme, a saline solution, a vitamin, a supplement, a dye (e.g., an acoustically activated dye or the like), a radiation therapeutic agent, a chemical therapeutic agent, a neurological medicine, a neurological preventative medicine, or combinations thereof) through the fluid conduit once the cranial implant device is implanted. To further illustrated, various therapies are optionally administered to subjects using the cranial implant devices disclosed herein, including, for example, antitumor, anti-seizure, anti-Parkinson, anti-hydrocephalus, anti-ADHD, anti-Alzheimer’s, anti-pain, anti-insomnia, anti-depression, anti-schizophrenia, energy-enhancing, mindenhancing, memory-enhancing, neuro-protective, anti-Huntington’s, anti-aging, and/or like.

[039] In certain embodiments, other or additional functional components are included in the cranial implant devices disclosed in this application, such as various non-fluid-based physiological condition intervention systems. Typically, the intercranial implantation of the cranial implant devices described herein is intended to be for an indefinite duration to permit therapeutic administration for as long as needed. This feature overcomes significant limitations of many pre-existing CED applications, which can only typically remain in place for at most 5-10 days due to the risk of infection over longer periods of time and/or do not have enough positive pressure to overcome flow resistance with the human brain.

[040] In some embodiments, a cranial implant housing is configured for intercranial implantation in a cranial opening of a subject. Typically, the cranial implant housing has a substantially anatomically-compatible shape in order to be essentially imperceptible to the naked eye upon implantation in a subject with no visible deformity. The cranial implant housing typically includes first and second surfacesand also includes a fluidic circuit that includes a cavity and a port that fluidly communicates with the cavity through the second surface. Optionally, the cavity and the port fluidly communicate with one another through other surfaces of the cranial implant housing. The cavity is generally configured to contain fluidic therapeutic agents (e.g., chemotherapeutic agents, immunological agents, etc.) that are pre-loaded in the cranial implant device prior to implantation and/or added post-implantation in a subject. In some embodiments, fluidic circuits include one or more fluidic channels operably connected to cavities and ports, including, for example, microfluidic channel networks. In certain other exemplary embodiments, cranial implant housings include multiple cavities that each comprise, or are capable of comprising, one or more fluidic therapeutic agents and/or other fluidic materials. In some embodiments, cranial implant devices include multiple ports that fluidly communicate with cavities through, for example, the second surface.

[041] A first surface of an implant device typically also includes a self-sealing access port (e.g., a septum or the like) disposed at least partially in or through the first surface. The self-sealing access port fluidly communicates with the cavity and is configured to repeatedly receive a syringe needle (e.g., a self-sealing syringe) through the scalp of a subject to add and/or remove fluidic therapeutic agents to/from the cavity. Suitable self-sealing access ports are commercially available from various suppliers, including, for example, Smiths Medical. In certain embodiments, self-sealing access ports have contoured shapes for tactile recognition following device implantation. In other embodiments, a protective barrier (e.g., a titanium plate or the like) is position below a given self-sealing access port in the cavity to prevent the syringe needle from damaging the implant device upon insertion.

[042] Implant devices also generally include pumps operably connected to fluidic circuits and disposed within implant cores. Essentially any type of pump configuration is optionally adapted for use in the implant devices disclosed herein, including gear pumps, vane pumps, hose pumps, centrifugal pumps, lobe pumps, diaphragm pumps, peristaltic pumps, positive displacement pumps, non-positive displacement pumps, and the like. In addition, a variety of actuators are optionally adapted to effect fluid conveyance using these pumps, including, for example, piezo electric motors, reciprocating motors, rotary motors, and the like. Pumps are configured to convey the fluidic therapeutic agent from a device cavity through a fluid conduit that fluidly communicates with the pump and the port, and the fluid conduit that fluidly communicates with the pump through the port disposed through the second surface. In some embodiments, for example, the fluid conduit (e.g., a catheter or other polymer tubing) is operably connected to the pump and extends from implant device through the port. In some embodiments, the fluid conduit is operably connected directly to the port. The pump is typically configured to maintain positive pressure gradient of the fluidic therapeutic agent at least proximal to an outlet of the fluid conduit (e.g., to effect convection-enhanced delivery of the fluidic therapeutic agent). To provide a measure of rigidity for implantation, fluid conduits are typically at least partially disposed within cannulas that are operably connected to cranial implant housings. In other exemplary embodiments, second surfaces of implant devices include 2, 3, 4, 5, or more ports that fluidly communicate with the fluidic circuits disposed within cranial implant housings. In these embodiments, the fluid conduits are typically operably connected to the ports and/or to the pump, for example, via a manifold or the like. In some embodiments, pumps are configured to deliver fluid with positive pressure, pulsatile flow into the brain parenchyma, the lateral ventricle, a potential space following resection, a feeding blood vessel, and/or an artificial cavity, such as a refillable bladder. In certain embodiments, pumps are configured to selectively remove, aspirate (e.g., with negative pressure), or syphon extraneous fluid in a reversible manner from brain parenchyma, lateral ventricle, a potential space, brain tumor cavity, and/or an artificial cavity (e.g., a refillable bladder). In some of these embodiments, fluid is syphoned and removed by percutaneous needle puncture for sampling (e.g., cell sampling) and/or pumped back to the site of origin once the fluid is, for example, reconditioned or the like. In some embodiments, pumps are synergistically paired with one or more remote imaging devices to monitor fluid distribution using, for example, wireless connectivity.

[043] In some embodiments, the present disclosure provides a safe and miniature device that enables a consistent and controllable low flow rate of liquid that can be delivered to a target location with long-term reliability. This can be achieved with multiple design principles, including hydrogels, electro-active polymers, microfluidic chips, and electroosmotic pumps. In particular, the electroosmotic (EO) pump allows for silent, low power consumption, and steady flow of, for example, water (e.g., deionized (DI) water) or the like, through an active element. In some embodiments, this active element is a porous cylinder that, when a voltage is applied across it, will move water towards the negative terminal (Figures 3A-E). The active electroosmotic element typically snuggly fits inside a silicone tube. The double action of the pump allows for two sets of cylindrical outlets on each end of the casing where one or multiple catheters can be connected to each end of the pump. These catheter(s) can then be placed inside the target location. The design of the pump involves two subsystems: (1 ) the internal bellow/active element system that moves a specified, sealed amount of DI water back and forth through the internal pump, and (2) the external housing that uses a set of valves on each side of the bellows to allow for the movement of the internal system to create suction or pressure to draw in and expel the desired therapeutics or other fluidic materials. The internal bellow/active element system, in some embodiments, comprises the active electroosmotic element that is snuggly fit inside a silicone tube, which is sandwiched on both sides with bellows. The external housing, in some embodiments, comprises valves, which plug each of the bellows’ exterior side openings to allow for the movement of the internal system to create suction or pressure to draw in and expel the desired therapeutics or other fluidic material, and the external case. In some embodiments, there is an internal sensing system that will sense when one side of the pump has reached its “empty” state (when all of the water is on the other side), by a contact switch that will touch the wire that applies the voltage across the active element. The bending of this sensing wire is typically precise, and the entire device is generally airtight and leak-proof with bio-compatible sealant, such as medical grade epoxy or silicone.

[044] To illustrate, Figures 3A-E schematically show electroosmotic pumps according to exemplary embodiments. As shown, electroosmotic (EO) pump 300 includes internal element 302 comprising active EO element 304 disposed at least partially within first housing 306 that comprises at least two openings 308. First bellow structure 310 is operably connected to first housing 306 and communicates with a first opening of the at least two openings 308. Second bellow structure 312 is operably connected to first housing 306 and communicates with a second opening of the at least two openings 308. Active EO element 304 is configured to convey at least a first fluidic material at least between first and second bellow structures 310 and 312 to effect movement of the first and second bellow structures 310 and 312 when internal element 302 comprises the first fluidic material. EO pump 300 also includes external element 314 comprising second housing 316 that comprises at least two orifices 318. Internal element 302 is at least partially disposed within second housing 316 such that when the first fluidic material is conveyed at least between first and second bellow structures 310 and 312 of internal element 302 and at least a first orifice 318 of second housing 316 communicates with a source of at least a second fluidic material, the second fluidic material is conveyed through the first orifice 318 and second housing 316 and out of at least a second orifice 318 of second housing 316. In some embodiments, EO pump 300 also includes at least one sensor element at least within sensory communication of the internal element and/or the external element. The sensor element is configured to sense a position of one or more components of the EO pump. Figures 3 D and E schematically show EO pumps 301 and 303, respectively, according to additional exemplary embodiments.

[045] Cranial implant devices typically also include attachment mechanisms or portions thereof (e.g., a luer lock-type connections or the like) operably connected, or connectable, to the cranial implant housing and/or fluid conduits. These attachment mechanisms are generally configured to attach fluid conduits to the cranial implant devices such that the fluids conduit fluidly communicate with the fluidic circuits and to minimize the risk of joints becoming disconnected after placement. [046] In addition, implant devices also typically include a controller (e.g., a microcontroller or the like) operably connected at least to pumps. Controllers are configured to selectively effect pumps to convey fluidic therapeutic agents (e.g., at selected dosages and at defined times) through the fluid conduit through ports from device cavities. Typically, controllers are configured for wireless connectivity so as to be remotely monitored, activated, and/or adjusted.

[047] Implant devices also include power sources operably connected to controllers and pumps. Essentially any suitable power source (e.g., a rechargeable power source) is optionally used, or adapted, for use to provide power to the components of the implant devices. In some exemplary embodiments, one or more batteries (e.g., zero-volt batteries, implantable batteries, rechargeable batteries, and/or the like) are used. Typically, power sources are rechargeable (e.g., a battery that is rechargeable via inductive or wireless charging) and safe wireless reactivation.

[048] Implant housings, pumps, controllers, and power sources of implant devices are typically fabricated from one or more MRI compatible materials, for example, to permit on-going MRI monitoring of a given course of treatment for a subject while implant devices remain implanted in subjects. Essentially any MRI compatible material is optionally used, or adapted for use, in manufacturing the cranial implant housings disclosed herein. In some embodiments, for example, the cranial implant housing comprises an MRI compatible polymer, an MRI compatible metal, an MRI compatible bioengineered material, or combinations thereof. To further illustrate, the cranial implant housing optionally includes medical-grade titanium, titanium mesh, porous hydroxyapatite (HA), polymethylmethacrylate (PMMA), polyether ether ketone (PEEK), porous polyethylene, cubic zirconia (CZ), or combinations thereof. In certain embodiments, cranial implant housings are fabricated from substantially translucent materials, for example, to facilitate visualization (e.g., via visual translucency and/or sonolucency) by the surgeon through the housing during and after implantation. Moreover, pumps, controllers, power sources, and other functional components are typically encased within cranial implant housings, for example, to prevent bodily fluids from contacting those components and/or to maximize use of dead space between the first and second surfaces of the housings. In certain embodiments, at least some implant device components are fabricated from non-MRI compatible materials. In these embodiments, those device components are typically selectively removable from the remainder of an implanted device to facilitate MRI processes. Device components (e.g., implant housings, pump components, and the like) are optionally formed by various fabrication techniques or combinations of such techniques including, e.g., 3D printing, cast molding, machining, stamping, engraving, injection molding, etching, embossing, extrusion, or other techniques well-known to persons of ordinary skill in the art.

[049] In some embodiments, implant devices include other functional components, such as non-fluid-based physiological condition intervention systems configured to transmit therapeutic signals from the functional component to the subject and/or a remote receiver through a non-fluid conduit. In certain embodiments, for example, implant devices include one or more detectors or sensors at least partially disposed within implant housings and operably connected at least to controllers. These detectors or sensors are typically configured to detect detectable signals or other information from the subject and/or the device. To illustrate, this information typically includes, for example, a volume of fluidic therapeutic agent disposed in a device cavity, a volume of fluidic therapeutic agent conveyed through the fluidic circuit, a pressure of the fluidic therapeutic agent within the fluidic circuit and/or proximal thereto (e.g., at an outlet to a fluid conduit, a leakage of the fluidic therapeutic agent from the fluidic circuit, a status of a power source (e.g., charge status), a device component malfunction, visual images of brain or brain cavity via an implanted imaging device, a detectable signal from the subject, and/or the like. Typically, the detectable signal from the subject is characteristic of at least one disease, condition or disorder. In certain embodiments, the detectable signal from the subject comprises image data. Typically, the fluid and the non-fluid conduits disclosed herein are configured for fluidic, electrical, magnetic, and optical communication between the functional components and the subject. In some embodiments, therapeutic signals include an electrical signal, a magnetic signal, an optical signal, or combinations thereof. In certain embodiments, the functional components are configured to provide acute neurological intervention comprising medicinal therapy, electro-stimulation therapy, radiation therapy, chemotherapy, or a combination thereof. Optionally, one or more of the functional components include, for example, a vital sign monitor, an optical coherence tomography (OCT) image monitor, a high definition camera, an intracranial pressure (ICP) monitor, an electroencephalography sensor (ECOG), a duplex ultrasound monitor, and/or a remote imaging monitor. Additional details regarding other functional components that are optionally adapted for use with the devices disclosed herein are found in, for example, WO 2017/039762 and WO 2018/044984, which are each incorporated by reference in their entirety.

[050] To further illustrate, implant devices optionally includes non-fluid-based physiological condition intervention systems that include non-fluid conduits (e.g., a sensor, detector, imaging device, and/or the like). In some embodiments, for example, non-fluid conduit includes an electrode operably connected to an implant housing, power source, and/or controller. The electrode is configured to selectively transmit one or more electrical signals to the subject, for example, as part of a course of therapy. In certain embodiments, at least a portion of the electrode is disposed within implant housing and/or extends from a second surface of an implant housing. In other exemplary embodiments, non-fluid conduits include at least one imaging device (e.g., a visual camera, an ultrasound device (e.g., a duplex ultrasound device), an optical coherence tomography (OCT) device, or the like) operably connected to an implant housing, power source, and/or controller. The imaging device is typically configured to selectively capture image data (e.g., low-definition image data and/or high-definition image data) from subjects. Typically, at least a portion of the imaging device is disposed within an implant housing and/or at least a portion of the imaging device extends from a second surface of an implant housing.

[051] The functional components include various embodiments. In some embodiments, for example, the functional component include at least one detector that is configured to detect information from the subject and/or the device. To illustrate, the functional component is optionally configured to provide neuron modulation via optic sensors in certain embodiments. In other exemplary embodiments, the functional component is configured for computerized monitoring of at least one physiological condition. Optionally, the functional component includes one or more of an intercranial pressure (ICP) monitor, a vital sign monitor, an imaging device (e.g., a camera, an optical coherence tomography (OCT) device, an ultrasound device, etc.), and the like. To further illustrate, the functional component optionally includes an electrical system, a remote imaging system, a radiation system (e.g., a seed therapy radiation system), a responsive neurostimulation system, and/or a neuromodulation system. Optionally, the functional component includes a medicine delivery device, an electrical signal delivery device, image capture device, radioactive seed device, energy storage device, and/or a computing device. In some embodiments, the functional component includes an electrical energy source, an electrical energy detector, electromagnetic energy source, and/or an electromagnetic energy detector. Typically, the electrical energy source is configured to generate an electrical signal and the electromagnetic energy source is configured to generate an optical signal, and the electromagnetic energy detector is configured to capture image data.

[052] In some embodiments cranial implant devices are optionally provided implanted in multiple subjects with wireless communications capability so as to communicate with a computer, via for example, a server. In some embodiments, this configuration is used to monitor randomized, controlled clinical trials. While not limited to any particular embodiment, such communication may be via electrical communication (such as via a USB cable) or via electromagnetic communication via Wi-Fi, Bluetooth, or the like. In one example, a computer may include a processor that executes software instructions for communicating with the functional component of a device. As such, remote monitoring of brain activity and/or tumor recurrence reduce healthcare costs associated with hospital-based imaging such as MRI and remove the need to have IVs placed for contrast administration - since the necessary dye are optionally delivered by cranial implant devices and imaging is also optionally done remotely by via cranial implant devices. While not limited to any particular embodiment, a computer may be a desktop computer, notebook computer, smart phone, tablet, a virtual reality device, a mixed reality device and server may be a cloud server or another format. Computers may communicate with implant devices, for example, functional components of implant devices, via the internet. Functional components may be activated remotely, for example, via signals generated in a computer. One example is analogous to a 24-hour cardiac heart monitor for which records heart activities for a certain time period. In this case, regrowth of tumor within the cavity would trigger an alarm for notifying the patient and/or healthcare provider. With certain implant device embodiments, the implant devices are optionally designed to monitor electrical activity, supranormal intracranial pressures, acute stroke-like bleeding, brain tumor recurrence, or aberrant seizure activity for a certain timeframe, and then at any time, the intervening physician, optionally downloads a recorded database of all activities related to specific intervention (i.e. subclinical seizure activity) that may be visualized on a 2-D and/or 3-D monitor screen. In certain embodiments, a computer displays data associated with signals generated by the functional component as it monitors patients in whom the device is attached (e.g., to simultaneously monitor courses of treatment for multiple patients, to simultaneously monitor clinical trials in which therapeutic agents are administer to patients via implant devices, etc.).

[053] To further illustrate, Figures 4A-C schematically show aspects of a cranial implant system according to exemplary embodiments. As shown, system 400 includes an implant device operably connected to a cellular device via BlueTooth connection. The cellular device is operably connected to a monitoring network via a cellular or Wi-Fi connection. As shown, information exchanged between the implant device and the monitoring network includes battery life, power transfer status, drug delivery rate, low drug reservoir, and the drug reservoir status, among other information. Additional exemplary aspects are schematically shown in Figure 4C.

[054] In some embodiments, the present disclosure provides a safe and miniature device that enables consistent sampling and analysis of fluid, as well as sampling of fluid for analysis. In some embodiments, this can be achieved with multiple design principles, including a two-way flow pump and microfluidic chips. In some of these embodiments, an implantable wireless biomarker microfluidic chip with two-way flow via inertial focusing can be used to sample and analyze fluid, such as CSF fluid from the brain. This use case enables early brain tumor recurrence to be detected. A microfluidic chip designed with very specific dimensions enables particles, such as biomarkers, to flow randomly through a straight channel and then separate by particle size in different locations in the microfluidic chamber via inertial focusing. Inertial focusing occurs because of the wall effect lift force and the shear-gradient lift force. These two forces are created because of the microfluidic chip’s channel and chamber specific geometry. The effect of these two forces cause the particles to be categorized by size in different lateral positions in the microfluidic channel over time. For example, biomarkers will be trapped in the above section of the chamber and ‘focused,’ whereas non-biomarkers would continue flowing through the central channel in the microfluidic chip. This entire process is generally dependent on the microfluidic chip’s channel and chamber specific geometry and the initial flow rate of the fluid. The design can achieve this specific initial flow rate with essentially any safe and miniature device that enables a consistent and controllable low flow rate of liquid that can be delivered to a target location with long-term reliability. This flow rate can be achieved with multiple design principles, including hydrogels, electro-active polymers, microfluidic chips, and electroosmotic pumps, including the electroosmotic pumps described herein. As one exemplary use case enables early brain tumor recurrence to be detected, this inertial focusing device can be combined with a medicine delivery device to both detect and treat brain tumor recurrence.

[055] In some embodiments, this disclosure provides a microfluidic device, comprising a body structure that comprises at least one channel that communicates with a least one chamber, wherein at least one cross-sectional dimension of the chamber is greater than at least one cross-sectional dimension of the channel such that when fluidic materials comprising particles are conveyed from the channel into the chamber, at least two different sized particles at least partially separate from one another in the chamber. In some embodiments, the microfluidic device further comprises an electroosmotic (EO) pump that communicates with the channel and/or the chamber.

[056] While the foregoing disclosure has been described in some detail by way of illustration and example for purposes of clarity and understanding, it will be clear to one of ordinary skill in the art from a reading of this disclosure that various changes in form and detail can be made without departing from the true scope of the disclosure and may be practiced within the scope of the appended claims. For example, all the methods, cranial implant devices, and/or component parts or other aspects thereof can be used in various combinations. All patents, patent applications, websites, other publications or documents, and the like cited herein are incorporated by reference in their entirety for all purposes to the same extent as if each individual item were specifically and individually indicated to be so incorporated by reference.