CROSS-REFERENCE TO RELATED APPLICATONS

[001] This application claims priority to U.S. Provisional Patent Application Ser. Nos. 62/963,357, filed January 20, 2020, the disclosure 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] Neuro-oncologists, neurosurgeons, and neuroplastic surgeons are all in need of a chronic method to deliver therapeutics directly to recurrent glioblastoma multiforme tumor sites in order to extend patient life. As such, convection-enhanced delivery (CED) is a direct (i.e., local) medicine delivery technique that has shown great promise for an otherwise challenging dilemma with respect to brain tumors and effective chemotherapy delivery. In summary, the CED technique in pre-existing form involves connecting the patient’s head directly to a tall intravenous pole with pressure-assisted flow to overcome resistance via several brain catheters placed through the scalp and small skull defects, and kept in place for just 5-10 days maximum due to the risk of infection. This pre-existing approach is able to generate a pressure gradient at the tip of an infusion catheter to deliver therapeutics directly through the interstitial spaces of the central nervous system (CNS), which has suggested improved survival with respect to standard chemotherapy for malignant brain tumors like glioblastoma by avoiding toxic metabolites observed with therapies like radiation and/or intravenous/oral chemotherapy. However, the limit of CED’s pre-existing applicability is the fact that there is no reliable delivery vehicle to allow CED to occur past 5-10 days, for example, in a way that would be chronic, safe, effective, allow the patient to be discharged from the hospital, and could avoid any form of visible deformity with the accompanying social stigmata of being treated for brain cancer.

SUMMARY

[004] This application discloses magnetic resonance imaging (MRI) compatible cranial implant devices (e.g., MRI Conditional in certain embodiments) 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, the present disclosure provides a magnetic resonance imaging (MRI) compatible cranial implant device. The device includes at least one cranial implant housing configured for intercranial implantation in at least one cranial opening of a subject, which cranial 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 device also includes at least one pump operably connected to the fluidic circuit, which 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 device also includes at least one controller operably connected at least to the pump, which controller is configured to selectively effect the 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, and at least one flexible polymer lithium-ion battery operably connected at least to the controller, wherein the cranial implant housing, the pump, the controller, and the flexible polymer lithium-ion battery are fabricated from one or more MRI compatible materials. Suitable flexible polymer lithium-ion battery are described in, for example, Langevin et al., “UV-cured gel polymer electrolytes with improved stability for advanced aqueous Li-ion batteries,” Chem Commun (Camb). 2019 Oct 29;55(87):13085-13088, which is incorporated by reference in its entirety.

[006] In one aspect, the present disclosure provides a magnetic resonance imaging (MRI) compatible cranial implant device. The device includes at least one cranial implant housing configured for intercranial implantation in at least one cranial opening of a subject, which cranial 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 device also includes at least one pump operably connected to the fluidic circuit, which 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, at least one controller operably connected at least to the pump, which controller is configured to selectively effect the 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, and at least one power source operably connected at least to the controller. The device also includes 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, and at least one light source (e.g., a low profile LED light) disposed proximal to the self-sealing access port, which light source is operably connected to the controller and/or the power source, which light source is configured to selectively illuminate and be visible through the scalp of the subject, wherein the cranial implant housing, the pump, the controller, and the power source are fabricated from one or more MRI compatible materials.

[007] In some of these embodiments, the cranial implant housing comprises a standardized form. In certain of these embodiments, the cavity comprises substantially all of the dead space within the cranial implant housing. In some of these embodiments, the fluid conduit comprises at least one catheter. In certain of these embodiments, one or more electrochemical sensors are operably connected to the controller and disposed at least proximal to the fluid conduit, which electrochemical sensors are configured to detect one or more electrochemical properties within the cranium of the subject when the cranial implant device is implanted in the cranial opening of the subject.

[008] In one aspect, the present disclosure provides a device that includes at least one self-sealing access port that is configured to receive one or more syringe needles through at least one layer of tissue of a subject when the device is implanted below the layer of tissue of the subject, and at least one light source operably connected, or connectable, to the self-sealing access port, which light source is operably connected, or connectable, to at least one power source, which light source is configured to selectively illuminate and be visible through the layer of tissue of the subject when the device is implanted below the layer of tissue of the subject. [009] In one aspect, the present disclosure provides a pump system that includes at least one reservoir configured to contain at least one fluidic material, which reservoir comprises at least a first opening, and at least one flow rate regulating bladder that comprises at least one housing that defines at least one chamber, at least one conductive diaphragm at least partially disposed within the chamber, at least a first electrode substantially disposed at least proximal to a first side of the conductive diaphragm, at least a second electrode substantially disposed at least proximal to a second side of the conductive diaphragm, and at least first and second openings that fluidly communicate with the chamber. The pump system also includes at least one pump comprising at least one inlet that fluidly communicates with the first opening of the reservoir and at least one outlet that fluidly communicates with the first opening of the bladder, which pump is configured to convey the fluidic material from the reservoir to the bladder when the reservoir contains the fluidic material, at least one fluid conduit that fluidly communicates with the second opening of the bladder, and at least one controller operably connected at least to the first and second electrodes of the bladder and the pump, which controller is configured to at least detect when the bladder is in a filling state in which the conductive diaphragm is in contact with neither the first or second electrode, when the bladder is in a full or emptying state in which the conductive diaphragm is in contact with the first electrode, and when the bladder is in an empty state in which the conductive diaphragm is in contact with the second electrode. In some embodiments, the pump is selected from the group consisting of: a piezoelectric pump, an electro-osmotic pump, a peristaltic pump, and a piezo peristaltic pump.

[010] In one aspect, the present disclosure provides a pump system that includes at least a first reservoir configured to contain at least a first fluidic material, which reservoir comprises at least a first opening, and at least a second reservoir that comprises at least one housing that defines at least one chamber, at least one diaphragm that separates the chamber into at least first and second chamber portions, at least a first opening that fluidly communicates with the first chamber portion, and at least a second opening that fluidly communicates with the second chamber portion, wherein the second chamber portion is configured to contain at least a second fluidic material. The pump system also includes at least one pump comprising at least one inlet that fluidly communicates with the first opening of the first reservoir and at least one outlet that fluidly communicates with the first opening of the first chamber portion, at least one fluid conduit that fluidly communicates with the second opening of the second reservoir, and at least one valve disposed substantially between the second opening of the second reservoir and an outlet of the fluid conduit. In addition, the pump system also includes at least one controller operably connected at least to the pump, which controller is configured to convey the first fluidic material from the first reservoir to the first chamber portion when the first reservoir contains the first fluidic material such that the second fluidic material is conveyed from the second chamber portion through the fluid conduit when the second chamber portion contains the second fluidic material. In some embodiments, wherein the pump is selected from the group consisting of: a piezoelectric pump, an electro-osmotic pump, a peristaltic pump, and a piezo peristaltic pump. In some embodiments, the valve comprises at least one ball valve.

[011] In one aspect, the present disclosure provides a pump system that includes at least a first branched channel network comprising a first merged channel that fluidly communicates with a first plurality of divided channels, at least a second branched channel network comprising a second merged channel that fluidly communicates with a second plurality of divided channels, wherein the second branched channel network fluidly communicates with the first branched channel network, and at least one pump operably connected at least to the first plurality of divided channels and the second merged channel. The pump system also includes at least one controller operably connected to the pump, which controller is configured to effect the pump to convey fluidic material out of the second plurality of divided channels from the first merged channel when first merged channel fluidly communicates with a reservoir that comprises the fluidic material.

[012] In one aspect, the present disclosure provides a pump system that includes at least one fluid conduit that comprises at least first and second openings, at least one pump operably connected to the fluid conduit, which pump comprises at least one rotational hub that comprises at least one protrusion and a plurality of independently movable pins, and at least one motor operably connected to the rotational hub, which motor is configured to rotate the rotational hub such that the protrusion sequentially moves individual pins in the plurality of independently movable pins into contact with the fluid conduit such that fluidic material is conveyed out of the second opening from the first opening when the first opening communicates with a reservoir that comprises the fluidic material.

[013] In one aspect, the present disclosure provides a pump system that includes at least one fluid conduit that comprises at least first and second openings, at least one pump operably connected to the fluid conduit, which pump comprises a plurality of independently movable pneumatic cylinders, and at least one controller operably connected to the plurality of independently movable pneumatic cylinders, which controller is configured to sequentially move individual pneumatic cylinders in the plurality of independently movable pneumatic cylinders into contact with the fluid conduit such that fluidic material is conveyed out of the second opening from the first opening when the first opening communicates with a reservoir that comprises the fluidic material.

[014] In one aspect, the present disclosure provides a pump system that includes at least one fluid conduit that comprises at least first and second openings, at least one pump operably connected to the fluid conduit, which pump comprises a plurality of independently movable piezo discs, and at least one controller operably connected to the plurality of independently movable piezo discs, which controller is configured to sequentially move individual piezo discs in the plurality of independently movable piezo discs into contact with the fluid conduit such that fluidic material is conveyed out of the second opening from the first opening when the first opening communicates with a reservoir that comprises the fluidic material.

[015] In another aspect, the present disclosure provides an ultrasonic wireless power transfer (WPT) device that includes at least one output receiver element operably connected to at least one implantable device, and at least one input transducer element operably connected to at least one power source, which input transducer element is configured to wirelessly transfer power to the output receiver element at least when at least one layer of tissue is disposed between the output receiver element and the input transducer element. In some embodiments, the output receiver element and/or the input transducer element comprise at least one piezo disk. [016] In one aspect, this disclosure provides a magnetic resonance imaging (MRI) compatible, convection-enhanced delivery (CED) cranial implant device at least one cranial implant housing configured for intercranial implantation in at least one cranial opening of a subject. The cranial 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 in which the cavity comprises, or is capable of comprising, at least one fluidic therapeutic agent. The device also includes at least one CED pump operably connected to the fluidic circuit. The CED 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 device also includes at least one controller operably connected at least to the CED pump. The controller is configured to selectively effect the CED 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. In addition, the device also includes at least one power source operably connected at least to the controller. The cranial implant housing, the CED pump, the controller, and the power source are fabricated from one or more MRI compatible materials. In certain embodiments, the cranial implant housing comprises a standardized form (i.e., off the shelf availability), whereas in other embodiments, the cranial implant housing comprises a form that is customized and patient-specific for the subject. Generally, the intercranial implantation is of an indefinite duration.

[017] In some embodiments, the fluidic therapeutic agent comprises an optogenetic protein, a stem cell, an immune cell, an antibody, an enzyme, a radiation therapeutic agent, a chemical therapeutic agent, a neurological medicine, a neurological preventative medicine, a neurological enhancer, or combinations thereof. In certain embodiments, the fluidic therapeutic agent comprises one or more therapies selected from the group consisting of anti-tumor, anti-seizure, anti-Parkinson, anti-Huntington, anti-hydrocephalus, anti-ADHD, anti-Alzheimer’s, anti-pain, anti-insomnia, anti- depression, anti-schizophrenia, energy-enhancing, mind-enhancing, neuro-protective, memory-enhancing, and combinations thereof.

[018] The fluidic circuit typically comprises one or more fluidic channels operably connected to the cavity and port. The cranial implant housing optionally comprises multiple cavities that each comprise, or are capable of comprising, one or more fluidic therapeutic agents and/or other fluidic materials. In some embodiments, the cranial implant includes multiple ports that fluidly communicate with the cavity through at least the second surface. In certain embodiments, the cranial implant housing comprises an MRI compatible polymer, an MRI compatible metal, an MRI compatible bioengineered material, or combinations thereof. In some embodiments, the cranial implant housing comprises one or more of medical-grade titanium, titanium mesh, porous hydroxyapatite (HA), polymethylmethacrylate (PMMA), polyether ether ketone (PEEK), porous polyethylene, cubic zirconia (CZ), or combinations thereof. In some instances, the cranial implant housing comprises a substantially translucent material.

[019] Typically, the cranial implant device includes at least one attachment mechanism or portion thereof operably connected, or connectable, to the cranial implant housing and/or the fluid conduit. The attachment mechanism or portion thereof is configured to attach the fluid conduit to the cranial implant housing such that the fluid conduit fluidly communicates with the fluidic circuit to enhance visible translucency and/or sonolucency.

[020] The CED pump, the controller, and the power source are encased within the cranial implant housing. In some embodiments, for example, the CED pump, the controller, and the power source and optionally one or more other device components are encased within the cranial implant housing to maximize use of dead space between the first and second surfaces. In certain embodiments, the CED pump comprises at least one electroactive polymer (EAP) valve-gated pump. Typically, the controller is configured for wireless connectivity so as to be remotely monitored, activated, or both. In some embodiments, the power source comprises at least one battery (e.g., a zero- volt battery, a rechargeable battery (e.g., Medtronic Model M957651A001 , etc.), and/or the like). In certain embodiments, the cranial implant device includes at least one self- sealing access port disposed at least partially in or through the first surface. The self sealing access port fluidly communicates with the cavity and is configured to receive one or more syringe needles (e.g., self-sealing syringe needles) through the scalp of the subject to add and/or remove the fluidic therapeutic agent to/from the cavity. In some of these embodiments, the self-sealing access port comprises a septum.

[021] In certain embodiments, the cranial implant device includes one or more detectors at least partially disposed within cranial implant housing and operably connected at least to the controller. The 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 the 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, a leakage of the fluidic therapeutic agent from the fluidic circuit, a status of the power source, a device component malfunction, visual images of brain or brain cavity via an implanted imaging device, and a detectable signal from the subject. Generally, the detectable signal from the subject is characteristic of at least one neurologically-related disease, condition or disorder. In certain embodiments, the detectable signal from the subject comprises image data.

[022] In some embodiments, the fluid conduit is operably connected to the port (e.g., during device fabrication). In other embodiments, fluid conduits are operably connected to ports in the operating room just prior to implantation. In certain embodiments, the fluid conduit delivers the fluidic therapeutic agent to 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. In some embodiments, the fluid conduit comprises a polymer tubing. In certain embodiments, the fluid conduit comprises a catheter. Typically, the fluid conduit is at least partially disposed within a cannula that is operably connected to the cranial implant housing. In some embodiments, the second surface of the cranial implant housing comprises 2, 3, 4, or 5 ports that fluidly communicate with one or more fluidic circuits disposed within the cranial implant housing. In some of these embodiments, the cranial implant device includes 2, 3, 4, or 5 fluid conduits operably connected to the ports for which is diagnostic or therapeutic in value.

[023] In certain embodiments, the cranial implant device includes at least one electrode operably connected, or connectable, to the cranial implant housing and/or the controller. The electrode is configured to selectively transmit one or more electrical signals to the subject (e.g., to effect flow alterations or low-level medicine quantities). In some embodiments, at least a portion of the electrode is disposed within the cranial implant housing. In certain embodiments, at least a portion of the electrode extends from the second surface of the cranial implant housing.

[024] In some embodiments, the cranial implant device includes at least one imaging device operably connected, or connectable, to the cranial implant housing and/or the controller, which imaging device is configured to selectively capture image data from the subject. In certain embodiments, the imaging device comprises a camera, ultrasound, or related technology. In some embodiments, at least a portion of the imaging device is disposed within the cranial implant housing. In certain embodiments, at least a portion of the imaging device extends from the second surface of the cranial implant housing. Optionally, the imaging device comprises an ultrasound or non- invasive imaging device. In some embodiments, the imaging device comprises an optical coherence tomography (OCT) device. In some embodiments, the image data comprises low-definition image data, whereas in other embodiments, the image data comprises high-definition image data. In some embodiments, the ultrasound has duplex capabilities to additionally detect changes in blood flow.

[025] In another aspect, the application discloses a magnetic resonance imaging (MRI) compatible, convection-enhanced delivery (CED) 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 housing comprises a substantially anatomically-compatible shape (e.g., to prevent visible deformity and optimal biocompatibility), 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 in which the cavity comprises, or is capable of comprising, at least one fluidic therapeutic agent. The cranial implant device also includes at least one CED pump operably connected to the fluidic circuit. The CED 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. In addition, cranial implant device also includes at least one power source operably connected at least to the CED pump. Typically, the cranial implant housing, the CED pump, and the power source are fabricated from one or more MRI compatible materials (e.g., to prevent interference with tumor bed surveillance).

[026] In another aspect, the application discloses 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. Typically, the cranial implant housing comprises a substantially anatomically-compatible shape (e.g., either one as off-the- shelf or another patient-specific form). 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 convection-enhanced delivery (CED) pump (e.g., an electroactive polymer (EAP) valve-gated 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. The cranial implant device also includes at least one power source (e.g., a zero-volt battery, wirelessly rechargeable battery, or the like) at least partially disposed within the cranial implant housing, which power source is operably connected to the functional components. Typically, 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, for example, the cranial implant housing, the functional components, and/or the power source comprises an MRI compatible polymer, an MRI compatible metal, an MRI compatible bioengineered material, or combinations thereof. Optionally, the cranial implant housing, the functional components, and/or the power source comprises one or more of medical- grade titanium, titanium mesh, porous hydroxyapatite (HA), polymethylmethacrylate (PMMA), polyether ether ketone (PEEK), porous polyethylene, cubic zirconia (CZ), or combinations thereof.

[027] 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 in which the cavity comprises, or is capable of comprising, the fluidic therapeutic agent. In certain embodiments, the CED pump is operably connected to the fluidic circuit. Typically, the fluidic circuit comprises one or more fluidic channels operably connected to the cavity and port. In some embodiments, the cranial implant housing includes 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 (e.g., self-sealing syringe needles) through the scalp of the subject to add and/or remove the fluidic therapeutic agent to/from the cavity, and/or cell pathology from nearby catheter placement.

[028] In certain embodiments, the functional components are configured to deliver one or more therapies to the subject selected from the group consisting of anti tumor, anti-seizure, anti-Parkinson, anti-Huntington, anti-hydrocephalus, anti-ADHD, anti-Alzheimer’s, anti-pain, anti-insomnia, anti-depression, anti-schizophrenia, energy enhancing, mind-enhancing, neuro-protective, memory-enhancing, and combinations thereof. In some embodiments, the functional components and the power source are encased within the cranial implant housing.

[029] In some embodiments, the cranial implant device includes 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 CED 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. The controller is typically configured for wireless connectivity so as to be remotely monitored, activated, adjusted, and/or charged. In some embodiments, for example, device infusion rated, dosage, and/or timing are changed via a wireless connection, typically depending upon certain treatment efficacy, patient symptoms, tumor growth, and/or vital signs. In certain of these embodiments, fluid conveyance involves remotely selecting a single or multiple catheters operably connected to a given implant device through which to pump fluid based, for example, on monitored flow and/or the like.

[030] The first functional component generally comprises one or more detectors at least partially disposed within cranial implant housing and operably connected at least to the controller. The 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.

[031] Typically, the fluid conduit and/or the non-fluid conduit extend from the cranial implant housing. In some embodiments, the fluid conduit and the non-fluid conduit are configured for fluidic, electrical, magnetic, imaging, and optical communication between the functional components and the subject. In some embodiments, the therapeutic signals comprise an electrical signal, a magnetic signal, an optical signal, an imaging signal, or combinations thereof. Optionally, 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, radiation therapy, or a combination thereof. In certain embodiments, one or more of the functional components comprises a vital sign monitor, an optical coherence tomography (OCT) image monitor, a high definition camera, an intracranial pressure (ICP) monitor, an electroencephalography sensor (ECOG), some radiation seeds for local therapy, and/or a remote imaging monitor.

[032] In some embodiments, the second functional component is configured to provide neuron modulation via optic sensors. Typically, 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 (e.g., a feeding blood vessel), neuron or ventricle of a brain. Optionally, the second functional component comprises at least one intercranial pressure (ICP) monitor. In some embodiments, the second functional component comprises at least one vital sign or brain function monitor. In certain embodiments, the second functional component comprises at least one imaging device. In some embodiments, the imaging device comprises a camera. In certain embodiments, the imaging device comprises an optical coherence tomography (OCT) device. In some embodiments, the imaging device comprises an ultrasound device with or without duplex capabilities. Optionally, the second functional component comprises an electrical system, a remote imaging system, a radiation therapy system, a responsive neurostimulation system, and/or a neuromodulation system. In some embodiments, the second functional component comprises a medicine delivery device, an electrical signal delivery device, image capture device, radioactive seed device, energy storage device, and/or a computing device. In certain embodiments, the second functional component comprises 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, the electromagnetic energy source is configured to generate an optical signal, and wherein the electromagnetic energy detector is configured to capture image data.

[033] In another aspect, the application discloses a method of treating a neurologically-related disease, condition or disorder of a subject that includes 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 cranial implant housing that comprises a substantially anatomically-compatible shape (either a standard (i.e., off-the- shelf) design or a customized (i.e., patient-specific) design), 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, in which the cavity comprises at least one fluidic therapeutic agent, and in which at least fluid conduit extends from the second surface and fluidly communicates with the fluidic circuit. The cranial implant device also includes at least one convection-enhanced delivery (CED) pump operably connected to the fluidic circuit, which CED pump is configured to convey the fluidic therapeutic agent from the cavity through the fluid conduit to maintain at least one positive pressure gradient of the fluidic therapeutic agent at least proximal to an outlet of the fluid conduit within a cranial cavity of the subject. The cranial implant device also includes at least one controller operably connected at least to the CED pump, which controller is configured to selectively effect the CED pump to convey the fluidic therapeutic agent through the fluid conduit. The cranial implant device additionally includes at least one power source operably connected at least to the controller. The cranial implant housing, the CED pump, the controller, and the power source are fabricated from one or more magnetic resonance imaging (MRI) compatible materials (e.g., to prevent interference with subsequent imaging). 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.

[034] In certain embodiments, the neurologically-related disease, condition or disorder comprises one or more of cancer (e.g., brain cancer), epilepsy, Parkinson’s disease, Huntington’s disease, hydrocephalus, attention deficit-hyperactivity disorder (ADHD), pain, Alzheimer’s disease, insomnia, depression, manic depression, and schizophrenia. Optionally, the fluidic therapeutic agent comprises an optogenetic protein, a stem cell, an immune cell, an antibody, an enzyme, a radiation therapeutic agent, a chemical therapeutic agent, a neurological enhancing medicine, a neurological preventative medicine, or combinations thereof. Typically, the method includes conveying the effective amount of the fluidic therapeutic agent to 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 of the subject.

[035] In some embodiments, at least one self-sealing access port is disposed at least partially in or through the first surface of the cranial implant housing, which self sealing access port fluidly communicates with the cavity, and the method comprises inserting a syringe needle (e.g., a self-sealing syringe needle) through the scalp of the subject (e.g., above or around the device) and through the self-sealing access port, and adding the fluidic therapeutic agent to the cavity (e.g., an embedded cavity). In certain embodiments, the controller is configured for wireless connectivity so as to be remotely monitored, activated, and/or adjusted, and the method comprises wirelessly sending and/or receiving information and/or instructions to/from the controller.

[036] In certain embodiments, the cranial implant device 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. In these embodiments, the method typically comprises detecting a volume of fluidic therapeutic agent disposed in the 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, a leakage of the fluidic therapeutic agent from the fluidic circuit, a status of the power source, a device component malfunction, and/or a detectable signal from the subject. In some embodiments, the cranial implant device comprises at least one intercranial pressure (ICP) monitor operably connected to the controller, and the method comprises monitoring the ICP of the subject using the ICP monitor (e.g., to detect pseudotumor cerebri, NPH, or obstructive hydrocephalus). In certain embodiments, the cranial implant device comprises at least one vital sign monitor operably connected to the controller, and the method comprises monitoring one or more vital signs of the subject using the vital sign monitor. In some embodiments, the cranial implant device comprises at least one imaging device operably connected to the controller, and the method comprises capturing image data from the subject using the imaging device. In some embodiments, the imaging device comprises an optical coherence tomography (OCT) device, and the method comprises capturing OCT image data from the subject using the OCT device. In certain embodiments, the imaging device comprises an ultrasound device with or without duplex capabilities, and the method comprises capturing ultrasound image data from the subject using the ultrasound device. In some embodiments, the method includes obtaining one or more MRI images of a cranial cavity of the subject.

[037] In another aspect, the application discloses a method of monitoring therapeutic agent administration in a plurality of subjects that includes surgically implanting at least one cranial implant device in each of the plurality subjects (e.g., to assist with clinical research and/or controlled trials). Each of the cranial implant devices comprises at least one cranial implant housing that comprises a substantially anatomically-compatible shape (either a standard (i.e., off-the-shelf) design or a customized (i.e., patient-specific) design), 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 at least one fluidic therapeutic agent, and wherein at least fluid conduit extends from the second surface and fluidly communicates with the fluidic circuit. The cranial implant device also includes at least one convection-enhanced delivery (CED) pump operably connected to the fluidic circuit. The CED pump is configured to convey the fluidic therapeutic agent from the cavity through the fluid conduit to maintain at least one positive pressure gradient of the fluidic therapeutic agent at least proximal to an outlet of the fluid conduit within a cranial cavity of a given subject. In certain embodiments, reversible pressure is used to create a vacuum for cytology retrieval or the like. The cranial implant device also includes at least one controller operably connected at least to the CED pump, which controller is configured to selectively effect the CED pump to convey the fluidic therapeutic agent through the fluid conduit, and for wireless connectivity so as to be remotely monitored, activated, and/or adjusted. The cranial implant device also includes at least one power source operably connected at least to the controller. The cranial implant housing, the CED pump, the controller, and the power source are fabricated from one or more magnetic resonance imaging (MRI) compatible materials. The method also includes conveying selected amounts of the fluidic therapeutic agent to one or more members of the plurality of subjects using the implanted cranial implant devices. In addition, the method also includes gathering data from one or more selected sets of members of the plurality of subjects using the wireless connectivity of the implanted cranial implant devices, thereby monitoring the therapeutic agent administration in the plurality of subjects (e.g., by way of a clinical trial investigation). In some embodiments, the data correlates with a measure of efficacy and/or toxicity of the therapeutic agent in the plurality of subjects. In certain embodiments, the data correlates with a measure of performance of the cranial implant devices in the plurality of subjects.

[038] In another aspect, the application discloses a surgical method that includes 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 cranial implant housing that comprises a substantially anatomically-compatible shape (either a standard (i.e., off-the-shelf) design or a customized (i.e., patient-specific) design), 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 in which the cavity comprises at least one fluidic therapeutic agent, and in which at least fluid conduit extends from the second surface and fluidly communicates with the fluidic circuit. The cranial implant device also includes at least one CED pump operably connected to the fluidic circuit. The CED pump is configured to convey the fluidic therapeutic agent from the cavity through the fluid conduit to maintain at least one positive pressure gradient of the fluidic therapeutic agent at least proximal to an outlet of the fluid conduit within a cranial cavity of the subject, and may also be used to maintain transient negative pressure for cell cytometry retrieval in some embodiments. The cranial implant device also includes at least one controller operably connected at least to the CED pump. The controller is configured to selectively effect the CED pump to convey the fluidic therapeutic agent through the fluid conduit. The cranial implant device also includes at least one power source operably connected at least to the controller. The cranial implant housing, the CED pump, the controller, and the power source are fabricated from one or more magnetic resonance imaging (MRI) compatible materials (e.g., to prevent inference with related imaging processes). [039] In another aspect, the application discloses a method of fabricating a cranial implant device that includes forming at least first and second portions of a cranial implant housing, wherein once assembled, the first and second portions form at least one cavity and at least one port that fluidly communicates with the cavity through at least one surface of the cranial implant housing to thereby generate at least one fluidic circuit, and wherein the first and second portions are formed from one or more magnetic resonance imaging (MRI) compatible materials. The method also includes positioning at least one convection-enhanced delivery (CED) pump relative to the first and/or second portions, wherein the CED pump is formed from one or more MRI compatible materials, positioning at least one controller relative to the first and/or second portions and operably connecting the controller to the CED pump, wherein the controller is formed from one or more MRI compatible materials, and positioning at least one power source relative to the first and/or second portions and operably connecting the power source to the controller, wherein the power source is formed from one or more MRI compatible materials. In addition, the method also includes attaching the first and second portions of a cranial implant housing to one another to generate the fluidic circuit and such that the CED pump, the controller, and the power source are encased within the first and second portions, and such that the cranial implant housing comprises a substantially anatomically-compatible shape, thereby fabricating the cranial implant device (e.g., which mirrors or corresponds to the natural curvature and thickness of the human skull).

[040] In another aspect, the application discloses an electroactive polymer (EAP) valve-gated pump that includes a top housing structure comprising at least a top surface in which at least one top orifice is disposed through the top surface. The pump also includes a bottom housing structure comprising a substantially concave fluid chamber having a top opening in which at least first and second fluid channels fluidly communicate with the fluid chamber. In addition, the pump also includes a membrane portion disposed between the top and bottom housing structures, which membrane portion encloses the concave fluid chamber when the top and bottom housing structures are attached to one another. The pump also includes an EAP-actuation mechanism (e.g., a dielectric EAP-actuation mechanism, an ionic EAP-actuation mechanism, etc.) operably connected to the membrane portion. The EAP-actuation mechanism is configured to displace the membrane portion to thereby effect fluid conveyance (e.g., in either direction through the pump). In some embodiments, the top and bottom housing structures comprise one or more reversible attachment features configured to reversibly attach the top and bottom housing structures to one another. In certain embodiments, the membrane portion comprises a silicon or other resealable membrane. In other exemplary embodiments, a cranial implant device comprises the pump. In these embodiments, at least a first fluid conduit is operably connected to the first fluid channel of the bottom housing structure and to a cavity disposed within the cranial implant device. In these embodiments, at least a second fluid conduit is also operably connected to the second fluid channel of the bottom housing structure and extends from a port disposed through at least one surface of the cranial implant device. In these embodiments, the pump is also operably connected to a controller disposed within the cranial implant device.

[041] In another aspect, the disclosure provides a convection-enhanced delivery (CED) cranial implant device that includes at least one cranial implant housing configured for intercranial implantation in at least one cranial opening of a subject (e.g., which typically matches the thickness of the removed or missing skull segment). The cranial implant housing comprises a substantially anatomically-compatible shape (either a standard (i.e., off-the-shelf) design or a customized (i.e., patient-specific) design), 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 CED cranial implant device also includes at least one CED pump operably connected to the fluidic circuit, which CED 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. In some embodiments, the device is configured to selectively effect reverse pressure application for transient suction for cell retrieval. The CED cranial implant device also includes at least one controller operably connected at least to the CED pump, which controller is configured to selectively effect the CED 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, and at least one power source operably connected at least to the controller. In addition, one or more of the cranial implant housing, the CED pump, the controller, the power source, or sub components thereof, are fabricated from one or more non-MRI compatible materials, which non-MRI compatible materials are selectively and reversibly removable from the CED cranial implant device when the CED cranial implant device is implanted in the subject.

[042] In another aspect, the disclosure provides a convection-enhanced delivery (CED) implant device that includes at least one implant housing configured for implantation in at least one opening (e.g., a thoracic opening, an abdominal opening, etc.) 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, wherein the cavity comprises, or is capable of comprising, at least one fluidic therapeutic agent. The CED implant device also includes at least one CED pump operably connected to the fluidic circuit, which CED 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 CED implant device also includes at least one controller operably connected at least to the CED pump, which controller is configured to selectively effect the CED 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, and at least one power source (e.g., a wirelessly rechargeable battery or the like) operably connected at least to the controller. In addition, the implant housing, the CED pump, the controller, and the power source are fabricated from one or more MRI compatible materials. BRIEF DESCRIPTION OF THE DRAWINGS

[043] 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, 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.

[044] Figure 1 schematically shows a method of attaching a left-sided, posterior, full-thickness skull resection outlined by a cut region and a CED cranial implant device being inserted into the resected portion of the removed or missing skull according to one exemplary embodiment.

[045] Figure 2 schematically shows the resulting intercranial implantation of the CED cranial implant device of Figure 1 with rigid fixation.

[046] Figure 3A schematically depicts a CED cranial implant device from a perspective view according to one exemplary embodiment.

[047] Figure 3B schematically shows the CED cranial implant device of Figure 3A from an exploded perspective view.

[048] Figure 3C schematically shows the CED cranial implant device of Figure 3A from an exploded top view.

[049] Figure 3D schematically shows the CED cranial implant device of Figure 3A from an exploded top view.

[050] Figure 3E schematically shows the CED cranial implant device of Figure 3A from a top view.

[051] Figure 4A schematically illustrates a component cavity from the cranial implant housing of the CED cranial implant device of Figure 3A from a bottom view. [052] Figure 4B schematically illustrates the component cavity of Figure 4A from a top view.

[053] Figure 4C schematically shows the component cavity of Figure 4A from a side view.

[054] Figure 4D schematically illustrates the component cavity of Figure 4A from a perspective view.

[055] Figure 5A schematically illustrates a fluidic therapeutic agent cavity from the cranial implant housing of the CED cranial implant device of Figure 3A from a perspective view.

[056] Figure 5B schematically shows the fluidic therapeutic agent cavity of Figure 5A from a side view.

[057] Figure 5C schematically depicts the fluidic therapeutic agent cavity of Figure 5A from a top view.

[058] Figure 6A schematically shows an electroactive polymer (EAP) valve gated pump from a side view according to one exemplary embodiment.

[059] Figure 6B schematically illustrates top and bottom housing structures from the pump of Figure 6A from an exploded perspective view.

[060] Figure 6C schematically illustrates the top housing structure from Figure 6B from a top view.

[061] Figure 6D schematically illustrates the top housing structure from Figure 6B from a side view.

[062] Figure 6E schematically illustrates the bottom housing structure from Figure 6B from a top view.

[063] Figure 6F schematically illustrates the top housing structure from Figure 6B from a side view.

[064] Figure 6G schematically shows a dielectric EAP-actuation mechanism from a top view according to one exemplary embodiment. [065] Figure 6H schematically shows an electroactive polymer (EAP) valve gated pump from a bottom view according to one exemplary embodiment.

[066] Figure 61 schematically shows the EAP valve-gated pump of Figure 6H from a bottom view.

[067] Figure 6J schematically shows the EAP valve-gated pump of Figure 6H from a side view.

[068] Figure 7 schematically shows a wireless communication network for gathering data from one or more subjects having intercranially implanted CED cranial implant devices according to one exemplary embodiment.

[069] Figure 8 schematically shows a CED cranial implant device being inserted into a resected portion of a removed or missing skull according to one exemplary embodiment.

[070] Figures 9A-C schematically show an electroactive polymer (EAP) configuration according to one exemplary embodiment. Figure 9A schematically shows the EAP from a sectional view. Figure 9B schematically shows a detailed view of the EAP from Figure 9A in the absence of an applied current. Figure 9C schematically shows a detailed view of the EAP from Figure 9A under the application of a current, which causes ions to shift and induce the polymer to bend, thereby effecting a pressure difference that induces fluid conveyance in the implant devices described herein.

[071] Figure 10 schematically depicts aspects of a cranial implant device according to an exemplary embodiment.

[072] Figure 11 schematically depicts aspects of a cranial implant device according to an exemplary embodiment.

[073] Figure 12 is a diagram that shows aspects of a cranial implant device according to an exemplary embodiment.

[074] Figure 13 schematically shows aspects of a piezoelectric pump system according to an exemplary embodiment. [075] Figure 14 schematically shows aspects of an electro-osmotic pump system according to an exemplary embodiment.

[076] Figure 15 schematically shows aspects of a cranial implant device that includes a piezoelectric pump according to an exemplary embodiment. As shown, the lid includes countersunk holes for thin plates and screws that fix the device to the implant. The reservoir includes inverted chambers that components below snug-fit into, thereby utilizing maximum free space. The pump is connected to the reservoir and bladder(s). The bladder or a number of bladders are typically installed in one of the chambers. Battery and charger is also positioned in one of the chambers. The last chamber is used by electronic components (not shown). The bottom case includes honeycomb shaped walls for impact-resistance, as well as small holes on the bottom surface for reservoir to be exposed to the intracranial pressure directly (not shown).

[077] Figure 16 schematically shows aspects of a fluid flow path of a cranial implant device according to an exemplary embodiment.

[078] Figure 17 schematically shows aspects of a fluid flow path of a cranial implant device according to an exemplary embodiment. As shown, the fluid path includes all of the space where the drug is stored and transported. A medical syringe containing the drug pierces the scalp to deliver drug to the reservoir, which is connected to the pump that delivers the drug to a flow-rate regulating component called a “bladder”. The drug then flows out of the bladder and through an orifice with a high resistance to flow rate. Finally, the drug enters the brain through a catheter.

[079] Figure 18 schematically shows aspects of a cavity or reservoir of a cranial implant device according to an exemplary embodiment. The reservoir typically utilizes the maximum free volume of the device. The volume of the reservoir generally determines how frequently a given patient needs to visit a physician for a drug refill. The drug is refilled by a needle, during which the patient’s scalp is punctured. In some embodiments, the entire device is 60 x 80 x 4 mm. In some embodiments, the reservoir is exposed to change in intracranial pressure (ICP). For example, if the patient is engaged in physical activity, the head orientation may result in a change in ICP, which could affect flow rate. Exposing the entire fluid System to ICP will minimize relative local pressure change. The reservoir typically contains a septum that self-seals after needle puncture during refill. In of these embodiments, a self-sealing polyisoprene septum is used as a piercing membrane. The reservoir is corrosion-resistant to the stored drug.

[080] Figure 19 schematically shows aspects of a cavity or reservoir of a cranial implant device according to an exemplary embodiment. As shown, the reservoir is encompassed by honeycomb-structured wall that is built for shear-resistance from outside impact. The device sits on a thin clear layer of PMMA implant. A lid with honeycomb shaped walls is fixated on top of all components, with peripheral countersunk holes for device fixture to the clear PMMA implant. The layer of PMMA implant underneath the device has small holes, where the reservoir is directly exposed to the intracranial pressure. The honeycomb walls create several “chambers” for device components. Any free space that has not been taken up by other components is typically used for the reservoir.

[081] Figure 20 schematically shows aspects of a method of fabricating a cavity or reservoir of a cranial implant device according to an exemplary embodiment. This exemplary fabrication method is for creating a hollow and elastic tube with a selected geometry. In the embodiment shown, the reservoir has a simple shape resembling a bent “E”, mimicking skull curvature and inverted chambers for components. In the method, molten wax is poured into 3D printed mold and cooled (step 1), the cooled wax model is dipped in a pool of latex, and the latex-coated wax is then taken out for latex to solidify (step 2), and the latex-coated wax is heated, melting wax away, thus leaving the latex coat (step 3). Other biocompatible materials are optionally used. In some embodiments, a reservoir unit is produced by 3D printing the desired reservoir shape using a support material, dipping the support material into latex, and submerging the latex-coated support material in a NaOH solution to dissolve the support material.

[082] Figure 21 is a diagram that schematically shows exemplary types of pumps that are optionally adapted for use in the cranial implant devices of the present disclosure. In some embodiments, pumps are MRI compatible, have a low and constant flow rate from about 1-5 pL/minute, have low power consumption, and have a thickness of 4 mm or less.

[083] Figure 22 schematically shows aspects of an electro-osmotic pump and reservoir of a cranial implant device according to an exemplary embodiment. Electro- osmotic pumps are often characterized by their extremely low power consumption, pulse free flow and conveniency to control [25]. They work by moving uncharged liquid relative to a stationary charged surface due to an externally applied electric field. These pumps take advantage of electroosmosis, a natural phenomenon inherent to a solid- liquid interface. These specific pumps have been used for drug delivery and can be fabricated using standard microfabrication technologies. In some embodiments, a ball valve as shown in the diagram is also used.

[084] Figure 23 schematically shows aspects of a piezoelectric pump of a cranial implant device according to an exemplary embodiment. Piezoelectrics are materials that can displace when a voltage is applied to it.[26] It can also generate a voltage when a mechanical stress is applied. Piezoelectric pumps operate on the principle that when an AC voltage is applied, a piezo element will vibrate, displacing fluid. These pumps are also small and piezoelectrics can be made out of ceramics. Ceramics are important because ceramics are MRI safe. However, there is a thin layer of conductive material on the piezos, which may impair the MR-image in certain applications. These pumps can generate, slow, pulsatile flow. With larger pump versions, flow rates of about 10 pL/min.

[085] Figure 24 is a diagram that schematically shows exemplary types of pumps that are optionally adapted for use in the cranial implant devices of the present disclosure.

[086] Figure 25 schematically shows aspects of a bladder of a cranial implant device according to an exemplary embodiment. The function of the bladder is to regulate flow rate. The inlet tube is connected to the pump, and the outlet tube is connected to an orifice with high resistance to flow. Pump flow rate will be higher than the orifice flow resistance, so that the pump can fill the bladder while the pump is on. A conductive membrane, at rest, contacts the bottom electrodes. As drug enters the bladder and fill the bladder, the membrane deforms upward, contacting the top electrode. Hence, the device will be able to detect when the bladder is 1) filling 2) full/ emptying, and 3) empty.

[087] Figure 26 schematically shows aspects of the operation of a bladder of a cranial implant device according to an exemplary embodiment. As shown, when the pump is turned on, the drug accumulates in the bladder and the diaphragm expands upward. The diaphragm is in contact with neither one of the electrodes, and the flow rate out of the bladder through an orifice increases over time. The flow resistance of the orifice is higher than pump flow rate, so that drug can accumulate in the bladder.

[088] Figure 27 schematically shows aspects of the operation of a bladder of a cranial implant device according to an exemplary embodiment. In this state the bladder is full, the diaphragm touches the upper electrodes, which sends a signal to the controller to turn the pump off. As a result, the elastomeric diaphragm pushes drug out, and because the pump is turned off, flow rate decreases slowly until there is no flow rate out of the orifice.

[089] Figure 28 schematically shows aspects of the operation of a bladder of a cranial implant device according to an exemplary embodiment. The bladder is now empty and the diaphragm (e.g., aluminized mylar, etc.) touches the bottom electrodes. The pump will be turned back on after a period of time turning the bladder back to the filling state. Increasing or decreasing the time taken before the pump re-activation will ultimately control total flow rate over time. The total volume of flow over one cycle is the volume difference between the diaphragm at rest state and full state. The bottom electrodes are offset from the bottom surface, and there is a dead volume of drug always left in the bladder.

[090] Figure 29 schematically shows aspects of a angiocath catheter of a cranial implant device according to an exemplary embodiment.

[091] Figure 30 schematically shows aspects of a catheter having electrochemical sensors of a cranial implant device according to an exemplary embodiment. The electrochemical sensors support real-time, continuous measurements of a wide range of physiological molecules in vivo via the catheters. In some embodiments, these sensors involve three gold wires 70 microns in diameter, have 500 mV and currents of nA to mA, have about 5 mm at the end of a wire (put chemistry right at about 5 mm right before implantation), and the wires are coated with plastic PGSE before the 5 mm mark. These sensors provide real time data of the concentration of drug delivered into the brain, which allows healthcare providers to monitor whether correct concentrations of the drug are delivered.

[092] Figure 31 schematically shows aspects of flexible batteries fabricated from aqueous gel polymer electrolytes (GPEs) of a cranial implant device according to an exemplary embodiment. In some embodiments, these batteries are made of a single material as thin and flexible as a contact lens. These typically includes a Wi-BS-based aqueous gel polymer electrolytes (GPEs) made via UV-mediated polymerization of water-soluble acrylates in the presence of WiBS.

[093] Figure 32 schematically shows a lithium ion button cell battery (specifications: 3.6V, 120 mAh, 24 mm diameter) of a cranial implant device according to an exemplary embodiment.

[094] Figure 33 schematically shows aspects of an ultrasonic wireless power transfer (WPT) component of a cranial implant device according to an exemplary embodiment. Essentially any WPT method is optionally used. In some embodiments, ultrasonic and/or inductive WPT is used. Ultrasonic is a method of transferring energy by using ultrasound to excite a piezoelectric disk, generating a voltage.

[095] Figure 34 schematically shows aspects of an ultrasonic wireless power transfer (WPT) component of a cranial implant device (e.g., to recharge device batteries, etc.) according to an exemplary embodiment. Ultrasound (US) is a commonly used mechanism for hospitals to image parts of the body. The fundamental principles behind US is the application of a voltage to a piezoelectric arrays generating the high pressure sound waves that propagate out of the US probe. [42] Another application for these sound waves is to excite another piezoelectric disk to achieve the opposite effect: having one piezo’s sound waves excite another piezo element (e.g., MRI safe materials (ceramic piezoelectric elements)), generating a voltage. [096] Figure 35 schematically shows aspects of an ultrasonic wireless power transfer (WPT) component according to an exemplary embodiment. In the embodiment shown, ultrasonic WPT uses two piezoelectric elements: a transducer (input) and receiver (output). The two piezo disks are made out of PZT-4, which is a ceramic, and are 2.5 cm in diameter. The transducer was manufactured with this disk adhered to an aluminum puck to aid in transferring the vibrations. The receiver disk was left bare. Castor oil was used as a medium to simulate the acoustic properties of soft tissue. The gap between the transducer and receiver is 3 mm, the thickness of the human scalp.

[097] Figure 36 schematically shows aspects of an ultrasonic wireless power transfer (WPT) component according to an exemplary embodiment.

[098] Figure 37 is a plot of an ultrasonic wireless power transfer (WPT) output voltage as a function of input frequency according to an exemplary embodiment. The input piezo-transducer was wired to a function generator with a constant 5 Vp-p output. The output frequency was varied from 900 kHz to 1.1 MHz. The peak received voltage was at 1.002 MHz with a peak-to-peak value of 1.84 Vp-p.

[099] Figure 38 schematically shows aspects of an inductive coil (30, 2.5” square loops out of 40 awg copper wire (0.0031 in diameter)) according to an exemplary embodiment.

[0100] Figure 39 schematically shows aspects of a hardware configuration of a cranial implant device according to an exemplary embodiment. The hardware is an integral part of the device because it controls and monitors the device. The main hardware components of this device are a microprocessor, voltage drive board, and a Bluetooth chip. The microprocessor allows the hardware to be programmed to execute various functions, such as controlling the frequency of the pump. The voltage drive board enables the hardware to drive high-voltage pumps from a low-voltage battery. The Bluetooth chip enables external communication and control between the hardware and an outside network.

[0101] Figure 40 schematically shows aspects of a hardware configuration of a cranial implant device according to an exemplary embodiment. In some embodiments, the hardware utilizes an Arduino to control the circuitry. A battery powers the circuity to adequately power the Arduino. The Bluetooth chip is directly connected to the microprocessor and enables external communication to the device. The hardware utilizes the three Arduino pin states (low impedance, high output voltage, low output voltage) to cycle between 0.7, 2.5, and 4.3V sent to the drive Board in this exemplary embodiment. The drive board steps up these voltages to +/-100V P-P.

[0102] Figure 41 is a plot of the real-time and average power consumption over time of a hardware configuration of a cranial implant device according to an exemplary embodiment. In particular, the graph shows the real-time and average power consumption of the hardware over a 2 hour period. The peaks show the current draw spike when the pump is activated. The current draw peaks at 80mA and settles at 50mA, with an average current draw during the day at 51.2mA. At this rate, the complete hardware setup can run 9.77 hours on a 9V battery.

[0103] Figure 42 schematically shows aspects of a wireless monitoring network using a cranial implant device according to an exemplary embodiment. In some embodiments, a phone alarm is included to alert a patient of a low drug reservoir volume. A passcode is optionally included for controlling the device in some embodiments.

[0104] Figure 43 schematically shows aspects of a wireless monitoring network using a cranial implant device according to an exemplary embodiment. In some embodiments, the device is able to communicate with a cell phone via a Bluetooth connection. Due to the nature of this low-range, wireless communication technology, the device utilizes the network capabilities of a cell phone in order to communicate with the monitoring network of the physician or patient. This sharing of data is important because the patient, family of patient, health care provider, and physician will all have real-time access to critical information regarding the patient.

[0105] Figure 44 is a screenshot from a mobile device that shows aspects of a wireless monitoring network using a cranial implant device according to an exemplary embodiment. Successfully enabled communication via Bluetooth between the device hardware and a cell phone. In the phone screenshot shown, strings of characters were sent to and from the cell phone. To achieve external control of the pump via Bluetooth, a user can change the state of the hardware by pressing a button, which would then be sent to the hardware’s microprocessor. The microprocessor will recognize certain strings and change states or send out information accordingly.

[0106] Figure 45 schematically depicts aspects of a cranial implant device according to an exemplary embodiment.

[0107] Figure 46 schematically depicts a ball valve of an electro-osmotic pump system of a cranial implant device according to an exemplary embodiment. In some embodiments, the electro-osmotic pump uses a valve to regulate flow and prevent backflow into the reservoir. The valve uses a polystyrene ball and a rubber catheter to provide a preload. The polystyrene ball has a similar density to water, allowing it to operate independent of gravity, meaning that the patient should be able to move freely without fear that the valve will open because of orientation. The tapered end of the valve seats the ball and blocks the fluid flow until the preload is overcome. All components are rubber or plastics, making this MRI-compatible. The independence from gravity and the materials used lowers the risk of this aspect of the fluid path significantly.

[0108] Figure 47 schematically depicts aspects of a bladder of a cranial implant device according to an exemplary embodiment. As shown, the rolled-up tube is where drug fills up. The elastic diaphragm pushes the tube back to an “empty” state.

[0109] Figure 48 schematically shows aspects of a piezoelectric pump according to an exemplary embodiment. Piezoelectric materials deform when a voltage is applied. The piezoelectric disk flexes at an applied frequency, displacing fluid in a chamber. The piezoelectric pump includes a pulsatile flow, and a variable frequency and voltage for slow flow rates. Ceramic piezoelectrics are MRI safe.

[0110] Figure 49 schematically shows aspects of a piezoelectric pump according to an exemplary embodiment.

[0111] Figure 50 schematically shows aspects of a valveless piezoelectric pump according to an exemplary embodiment. As shown, the bifurcation valveless design includes a bifurcating tree design acts like a valve with different flow resistances between dividing and merging flow directions. The piezo disk causes vibration, exciting the fluid in one direction. In some embodiments, the pump is manufactured using softlithography and can be made in the micrometer scale. In some embodiments, the piezo disk is operated at 220 V, 0-100 Hz[20], has a thickness of 230 pm, and achieves a flow rate of ~10pL/min @ 35 Hz.

[0112] Figure 51 schematically shows aspects of a valveless piezoelectric pump (circuit: 0-4.5 V, 0-40 Hz) according to an exemplary embodiment.

[0113] Figure 52 schematically shows aspects of a pin-CAM peristaltic pump according to an exemplary embodiment. As shown, the pinhead geometry follows the diameter of the tubing to maximize surface and minimize stress.

[0114] Figure 53 schematically shows aspects of a pin-CAM peristaltic pump according to an exemplary embodiment. As shown, the pump includes soft silicon tubing, a stainless steel bearing, and 3D printed pins, CAM, and casing.

[0115] Figure 54 schematically shows aspects of a linear piezo-peristaltic pump according to an exemplary embodiment. As shown, the stacked piezo discs are configured to move fluid through the tube.

[0116] Figure 55 schematically shows aspects of a linear piezo-peristaltic pump according to an exemplary embodiment.

[0117] Figure 56 is a screenshot from an application on a mobile phone that shows aspects of a wireless monitoring network using a cranial implant device according to an exemplary embodiment. The application receives phone notifications when the status of the device hardware changes. The status of the device hardware can also be changed via the phone.

[0118] Figure 57 schematically a ring of LED lights (5702) disposed around a septum (5700) of a cranial implant device according to an exemplary embodiment.

DEFINITIONS

[0119] 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.

[0120] 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.

[0121] 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.

[0122] 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).

[0123] 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.

[0124] 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).

[0125] 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.

[0126] 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.

[0127] 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.

[0128] Subjec 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.

[0129] 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.

DETAILED DESCRIPTION

[0130] This application discloses magnetic resonance imaging (MRI) compatible cranial implant devices (e.g., configured for convection-enhanced delivery (CED) in certain embodiments), pump assisted drug delivery systems, and related methods for performing a wide array of therapeutic and/or monitoring applications that bypass the blood brain barrier. 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. 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. Additional details related to cranial implant devices that are optionally used or adapted for use with the devices and other aspects disclosed herein are also described in, for example, W02020006240, EP3344192, and WO2018044984, which are each incorporated by reference in their entirety. [0131] By way of overview, Figures 1 and 2 schematically show the insertion of cranial implant device 100 (e.g., fabricated from MRI-compatible materials) in resected or missing portion 102 of skull 104 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 8 also schematically shows CED cranial implant device 800 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. As shown, cranial implant device 100 includes cranial implant housing 106, which includes a form or shape that is customized for missing or resected portion 102 of skull 104. 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 patient-specific 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. As also shown, cranial implant device 100 also includes functional component 108, which fluidly communicates with fluid conduit 110. Fluid conduit 110 is typically of a selected length and disposed at an angle relative to cranial implant housing 106 such that an outlet of fluid conduit 110 is positioned at a desired location within the cranial cavity of skull 104 (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 component 108 typically includes a fluid-based physiological condition intervention system that includes a convection- enhanced delivery (CED) 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 fluid conduit 110 once cranial implant device 100 is implanted. To further illustrated, various therapies are optionally administered to subjects using the cranial implant devices disclosed herein, including, for example, anti tumor, anti-seizure, anti-Parkinson, anti-hydrocephalus, anti-ADHD, anti-Alzheimer’s, anti-pain, anti-insomnia, anti-depression, anti-schizophrenia, energy-enhancing, mind enhancing, memory-enhancing, neuro-protective, anti-Huntington’s, anti-aging, and/or like.

[0132] 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.

[0133] To further illustrate, Figures 3-5 schematically depict additional aspects of the MRI compatible CED cranial implant devices disclosed herein. As shown, CED cranial implant device 200 includes cranial implant housing 202, which in this exemplary embodiment has a standardized form, for example, for ease of manufacture. In this embodiment, cranial implant housing 202 is schematically shown as having a generally circular form (e.g., with a curvature matching the human skull). Essentially any standardized form is optionally utilized (e.g., elliptical, square, rectangular, triangular, and the like).

[0134] As shown, cranial implant housing 202 is configured for intercranial implantation in a cranial opening of a subject. Typically, cranial implant housing 202 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. Cranial implant housing 202 includes first and second surfaces, 204 and 206, respectively. Cranial implant housing 202 also includes a fluidic circuit that includes cavity 208 and port 213 that fluidly communicates with cavity 208 through second surface 206. Optionally, cavity 208 and port 213 fluidly communicate with one another through other surfaces of cranial implant housing 202. Cavity 208 is configured to contain fluidic therapeutic agents (e.g., chemotherapeutic agents, immunological agents, etc.) that are pre-loaded in cranial implant device 200 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, second surface 206.

[0135] First surface 204 typically also includes self-sealing access port 218 (e.g., a septum (e.g., polyisoprene, etc.) or the like) disposed at least partially in or through first surface 204. Self-sealing access port 218 fluidly communicates with cavity 208 and is configured to repeatedly receive syringe needle 220 (e.g., a self-sealing syringe) through the scalp of the subject to add and/or remove fluidic therapeutic agents to/from cavity 208. 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 self-sealing access port 218 in cavity 208 to prevent syringe needle 220 from damaging CED cranial implant device 200 upon insertion.

[0136] Cranial implant device 200 also includes CED pump 210 operably connected to the fluidic circuit and disposed within the implant core in this exemplary embodiment. Essentially any type of pump configuration is optionally adapted for use in the cranial 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. CED pump 210 is configured to convey the fluidic therapeutic agent from cavity 208 through a fluid conduit (not shown) that fluidly communicates with CED pump 210 and port 212, and fluid conduit 211 that fluidly communicates with CED pump 210 through port 213 disposed through second surface 206. In some embodiments, for example, fluid conduit 211 (e.g., a catheter or other polymer tubing) is operably connected to CED pump 210 and extends from cranial implant device 200 through port 213. In some embodiments, fluid conduit 211 is operably connected directly to port 213. CED pump 210 is 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 surface 206 includes 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 CED pump 210, 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. [0137] The present disclosure also provides electroactive polymer (EAP) valve gated pumps (e.g., having dielectric or ionic EAP actuation mechanisms) that are optionally used in the CED cranial implant devices described herein or in essentially any other application to effect fluid conveyance (e.g., in other types of implantation devices to deliver therapeutic agents to parts of a patient’s body, other than the brain). To further illustrate, Figures 9A-C schematically show an EAP configuration according to one exemplary embodiment. EAP powered valve-gated pumps, or other types of pumps, motors, or other related components, are typically fabricated from MRI- compatible materials (e.g., a transparent photopolymer or other material described herein or otherwise known to persons of ordinary skill in the art). The pumps are optionally configured to convey fluids at a variety of flow rates controlled, adjusted, and/or monitored remotely. In some embodiments where EAP valve-gated pumps are included in CED cranial implant devices, for example, relatively low flow rates of less than about 5 pL/minute (e.g., about 4 pL/minute, about 3 pL/minute, about 2 pL/minute, about 1 pL/minute) are used to maintain a constant pressure gradient at the site of a therapeutic application.

[0138] To further illustrate, Figure 6 schematically shows exemplary EAP valve gated pump 300. In Figure 6A, for example, EAP valve-gated pump 300 is operably connected to catheters 302 and 304 via attachment mechanisms 306 and 308, respectively (shown as luer lock-type connections). As also shown, EAP valve-gated pump 300 includes top housing structure 310, which includes top surface 312 having top orifice 314 disposed through top surface 312. EAP valve-gated pump 300 also includes bottom housing structure 316, which includes substantially concave fluid chamber 318 having top opening 320. As also shown, first and second fluid channels 322 and 324, respectively, fluidly communicate with fluid chamber 318. Although not within view, EAP valve-gated pump 300 also includes a membrane portion (e.g., a silicon membrane or the like) disposed between the top and bottom housing structures. The membrane portion encloses concave fluid chamber 318 when the top and bottom housing structures 310 and 316, respectively, are attached to one another.

[0139] In certain embodiments, dielectric EAP-activation mechanisms are used with EAP valve-gated pump 300 to effect fluid conveyance. Optionally, ionic EAP- activation mechanisms are adapted for use. Figure 6G schematically shows dielectric EAP-actuation mechanism 330. As shown, dielectric EAP-actuation mechanism 330 includes copper tap 332, acrylic frame 334, VHB membrane 336, and copper or carbon grease 338. EAP-actuation mechanism 330 is typically attached to the membrane portion mentioned above (e.g., a silicon membrane or the like). When the EAP-actuation mechanism 330 is actuated and contracts, the silicon membrane is displaced, thereby causing fluid to flow through pump 300. Electrical connections to EAP valve-gated pump 300 are not shown in the figures, but are well-known to persons having ordinary skill in the art. In some embodiments, for example, electrical wiring is disposed through top orifice 314 of EAP valve-gated pump 300. To further illustrate, Figures 6H-J schematically show electroactive polymer (EAP) valve-gated pump 340.

[0140] In some embodiments, top and bottom housing structures 310 and 316, respectively, include reversible attachment features 326 (shown as corresponding threaded regions) configured to reversibly attach top and bottom housing structures 310 and 316 to one another.

[0141] 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.

[0142] In addition, cranial implant device 200 also includes controller 214 (e.g., a microcontroller or the like) operably connected at least to CED pump 210. Controller 214 is configured to selectively effect CED pump 210 to convey the fluidic therapeutic agent (e.g., at selected dosages and at defined times) through the fluid conduit through port 213 from cavity 208. Typically, controller 214 is configured for wireless connectivity so as to be remotely monitored, activated, and/or adjusted.

[0143] Cranial implant device 200 also includes power source 216 operably connected controller 214 and CED pump 210. 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 cranial implant device 200. 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.

[0144] Cranial implant housing 202, CED pump 210, controller 214, and power source 216 of cranial implant device 200 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 cranial implant device 200 remains implanted in the subject. 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, CED 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. [0145] In some embodiments, cranial implant device 200 includes 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, cranial implant device 200 includes one or more detectors or sensors at least partially disposed within cranial implant housing 202 and operably connected at least to controller 214. 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 cavity 208, 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 fluid conduit 211 , a leakage of the fluidic therapeutic agent from the fluidic circuit, a status of power source 216 (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 neurologically-related 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.

[0146] To further illustrate, cranial implant device 200 optionally includes non fluid-based physiological condition intervention systems that include non-fluid conduit 215 (e.g., a sensor, detector, imaging device, and/or the like). In some embodiments, for example, non-fluid conduit 215 includes an electrode operably connected to cranial implant housing 202, power source 216, and/or controller 214. 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 cranial implant housing 202 and/or extends from second surface 206 of cranial implant housing 202. In other exemplary embodiments, non-fluid conduit 215 includes 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 cranial implant housing 202, power source 216, and/or controller 214. 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 cranial implant housing 202 and/or at least a portion of the imaging device extends from second surface 206 of cranial implant housing 202.

[0147] 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.

[0148] To further illustrate, Figure 7 schematically illustrates that CED cranial implant devices 100 are optionally provided implanted in multiple subjects with wireless communications capability so as to communicate (as indicated by dashed-lines 400) with a computer 403, via for example, a server 401. 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, computer 403 may include a processor that executes software instructions for communicating with the functional component 108 of device 100. 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 CED cranial implant devices 100 and imaging is also optionally done remotely by via CED cranial implant devices 100. While not limited to any particular embodiment, computer 403 may be a desktop computer, notebook computer, smart phone, tablet, a virtual reality device, a mixed reality device and server 401 may be a cloud server or another format. Computer 403 may communicate with CED cranial implant devices 100, for example, functional components 108 of CED cranial implant devices 100, via the internet. Functional components 108 may be activated remotely, for example, via signals generated in computer 403. 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 CED cranial 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, computer 403 display data associated with signals generated by the functional component 108 as it monitors patients in whom the device 100 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 CED cranial implant devices 100, etc.).

[0149] 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.