Patent Description:
The present invention relates generally to implantable medical devices useful in cell and/or tissue therapy applications and relates more particularly to systems and methods for controlling oxygen delivery to cells that are implanted in a subject using implantable medical devices.

Implantable medical devices (or "implant devices") are commonly-employed tools used in the treatment of various diseases, disorders, and/or conditions. Some implant devices comprise therapeutic cells and/or tissues that are encapsulated within an implantable container or capsule. The implantable container or capsule is typically designed to allow cells and/or tissues to produce a desired therapeutic and to disseminate the produced therapeutic to the patient while, at the same time, limiting an immunological response.

An example that illustrates the need for cell or tissue implantation is the development of cellular therapies for the treatment of diabetes. Currently, cell-based treatment options for diabetes treatment include whole pancreas organ transplant or transplant of pancreatic islets of Langerhans. However, because of the need for lifelong immunosuppressive treatment, these therapies are typically reserved for patients with the most difficult to treat Type <NUM> diabetes, particularly those who are already receiving immunosuppressive therapy as a result of a previous or concurrent organ transplant.

To address this shortcoming, containers or capsules have been developed that enable the implantation of islets and other tissues without the need for immunosuppression. For example, some currently available cell capsules incorporate an immunoisolating membrane that protects allogenic encapsulated tissue from the host immune system. Unfortunately, however, such an immunoisolating membrane also prevents vascularization of the encapsulated tissue, thereby making the delivery of essential gases to the encapsulated tissue and the removal of waste gases therefrom more difficult. As a result, such approaches have ultimately failed to realize the anticipated benefits due, in part, to limitations in oxygen delivery to the encapsulated cells.

In an attempt to address the above-noted limitations in oxygen delivery to implanted cells, several methods for delivering oxygen to cell capsules are being developed. These methods include the periodic injection of compressed gaseous oxygen through the skin to an implanted device, the delivery of oxygen to cell capsules through a percutaneous catheter, the implantation of chemical oxygen generators, and the implantation of electrochemical oxygen generating devices.

An example of an approach that involves the periodic injection of compressed gaseous oxygen through the skin to an implanted device containing cells is disclosed in <CIT>. More specifically, according to the aforementioned patent, there is disclosed a method for replenishing gas in a subcutaneously implanted medical device containing functional cells, the method comprising: inserting at least one needle, adapted to penetrate the skin and connecting a subcutaneously implanted medical device; connecting the inserted at least one needle to a gas replenishing apparatus; extracting gas from a gas reservoir in the implanted device into the gas replenishing apparatus; sensing oxygen level in the extracted gas; calculating the amount of gas needed for replenishing oxygen in the reservoir based on the sensed oxygen level in the extracted gas; and supplying gas from a gas tank in the gas replenishing apparatus to the gas reservoir in the implanted device.

The present inventor believes that the above approach has certain limitations. For example, the injection of pressurized oxygen requires that the user pierce the skin on a periodic basis and also requires periodic replacement of the septum in the device. Also, the failure to properly penetrate the septum with the needle could introduce gaseous oxygen to unwanted areas of the body, which may be hazardous. Additionally, the percutaneous delivery of oxygen carries a risk of infection, and associated devices are undesirably exposed to the environment. Moreover, importantly, the oxygen level in the gas reservoir is not sensed on a continuous or automatic basis, but rather, is only sensed when the needle is inserted by an operator into the gas reservoir. According to the above-discussed patent, the insertion of the needle into the gas reservoir may be as infrequent as once every two weeks. As can be appreciated, with such infrequent monitoring of the oxygen levels, it is possible that dangerously low or high levels of oxygen may not be sensed, and addressed, in a timely fashion.

An example of an approach that involves the use of an implanted electrochemical oxygen generator to provide oxygen to an implant device containing cells is disclosed in <CIT>. More specifically, according to the aforementioned patent, there is disclosed a system for gas treatment of a cell implant, the system including, in one embodiment, (i) an electrochemical device configured to output a first gas, such as gaseous oxygen (ii) a cell containment subsystem comprising a first chamber configured to receive cells, and (iii) a gas conduit for conveying the first gas from the electrochemical device to the first chamber, the gas conduit being coupled at one end to the electrochemical device and at an opposite end to the first chamber. According to another embodiment, the cell containment subsystem includes both a gas chamber and cell chambers on one or both sides of the gas chamber. In the aforementioned embodiment, the gas chamber receives the first gas from the electrochemical device, and the first gas is then delivered from the gas chamber to the one or more cell chambers.

The amount of oxygen that is provided in a system of the type described above should ideally be exactly equal to what is needed to sustain the respiratory needs of all of the implanted cells and to allow for increased cell density in the cell containment subsystem. However, in practice, matching the amount of oxygen that is needed with the amount of oxygen that is provided is difficult to accomplish. In those cases where too little oxygen is provided, the implanted cells may die or fail to perform their full functions. On the other hand, because a fully implanted device typically has no percutaneous vent for unused gas, in those cases where too much oxygen is provided, the gas pressure experienced by the cell containment subsystem may be excessive. In fact, in some instances, the gas pressure may become sufficiently great as to cause the cell containment subsystem to swell and to be at a significant risk for rupture.

Another example of an approach that involves the use of an implanted electrochemical oxygen generator to provide oxygen to an implant device containing cells is disclosed in <CIT>. More specifically, according to the aforementioned publication, there is disclosed an encapsulation device system for therapeutic applications, such as, but not limited to, regulating blood glucose. The system may comprise an encapsulation device with a first oxygen sensor integrated inside the device and a second oxygen sensor disposed on an outer surface of the device, wherein the sensors allow for real-time measurements (such as oxygen levels) related to cells (e.g., islet cells, stem cell derived beta cells, etc.) housed in the encapsulation device. The system may also feature an exogenous oxygen delivery system operatively connected to the encapsulation device via a channel, wherein the exogenous oxygen delivery system is adapted to deliver oxygen to the encapsulation device.

As can be appreciated, the approach described in the aforementioned PCT publication requires the use of oxygen sensors. However, oxygen sensors are typically sophisticated devices that rely on complicated techniques like fluorescence decay or voltammetric sensing (i.e., Clark electrode) to selectively detect a particular chemical species, in this case, oxygen. Moreover, an oxygen sensor may not give sufficient feedback to the control system regarding excessive gas pressure or sudden leaks.

Other documents that may be of interest include the following: <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; and <NPL>).

It is an object of the present invention to provide a novel system for controlling oxygen delivery to implanted cells.

According to one aspect of the invention, there is provided a system for controlling oxygen delivery to a cell implant, the system comprising (a) a water electrolyzer, the water electrolyzer being configured to generate gaseous oxygen with a variable output; (b) a first cell capsule, the first cell capsule comprising a cell chamber adapted to hold cells; (c) a first gas conduit, the first gas conduit fluidically coupled to the water electrolyzer and to the first cell capsule, whereby gaseous oxygen generated by the water electrolyzer is delivered to the first cell capsule; (d) a first total fluid pressure sensor, the first total fluid pressure sensor being placed so as to sense the total fluid pressure within the cell chamber of the first cell capsule; and (e) a controller, the controller being electrically coupled both to the first total fluid pressure sensor and to the water electrolyzer, wherein the controller is configured to control the variable output of the water electrolyzer based on one or more sensed total pressure readings from the first total fluid pressure sensor.

In a more detailed feature of the invention, the first total fluid pressure sensor may be disposed within the first cell capsule.

In a more detailed feature of the invention, the first cell capsule may comprise a gas compartment and a cell compartment, and the gas compartment and the cell compartment may be in gas communication with one another.

In a more detailed feature of the invention, the first total fluid pressure sensor may be disposed within the gas compartment of the first cell capsule.

In a more detailed feature of the invention, the first total fluid pressure sensor may be disposed outside of the first cell capsule.

In a more detailed feature of the invention, the first gas conduit may be tee-shaped, with a first end of the gas conduit fluidically coupled to the water electrolyzer, with a second end of the gas conduit fluidically coupled to the first total fluid pressure sensor, and with a third end of the gas conduit fluidically coupled to the first cell capsule.

In a more detailed feature of the invention, the system may further comprise a second gas conduit, and the second gas conduit may have a first end fluidically coupled to the water electrolyzer and a second end fluidically coupled to the first total fluid pressure sensor.

In a more detailed feature of the invention, the system may further comprise a second gas conduit, and the second gas conduit may have a first end fluidically coupled to the first cell capsule and a second end fluidically coupled to the first total fluid pressure sensor.

In a more detailed feature of the invention, the system may further comprise a second cell capsule, the second cell capsule may have a cell chamber adapted to hold cells, and the first gas conduit may be further fluidically coupled to the second cell capsule, whereby gaseous oxygen generated by the water electrolyzer may be delivered to the second cell capsule.

In a more detailed feature of the invention, the system may further comprise a second total fluid pressure sensor, the second total fluid pressure sensor may be electrically coupled to the controller, the gas conduit may be a manifold comprising a first end fluidically coupled to the water electrolyzer, a second end fluidically coupled to the first cell capsule, a first branch fluidically coupled to the first total fluid pressure sensor, and a second branch fluidically coupled to the second total fluid pressure sensor, and the gas conduit may be constricted between the first and second branches and may have an opening sized so that a difference in pressures sensed by the first and second total fluid pressure sensors is indicative of fluid flow therepast.

According to another aspect of the invention, there is provided a system for controlling oxygen delivery to a cell implant, the system comprising (a) a water electrolyzer, the water electrolyzer being configured to generate gaseous oxygen with a variable output; (b) a first cell capsule, the first cell capsule comprising a cell chamber adapted to hold cells; (c) a first total fluid pressure sensor; (d) a first gas conduit, the first gas conduit fluidically coupled to the water electrolyzer and to the first total fluid pressure sensor; (e) a second gas conduit, the second gas conduit fluidically coupled to the first total fluid pressure sensor and to the first cell capsule, whereby gaseous oxygen generated by the water electrolyzer is delivered to the first cell capsule via the first gas conduit, the first total fluid pressure sensor, and the second gas conduit; and (f) a controller, the controller being electrically coupled both to the first total fluid pressure sensor and to the water electrolyzer, wherein the controller is configured to control the variable output of the water electrolyzer based on one or more sensed total pressure readings from the first total fluid pressure sensor.

It is also an object of the present invention to provide a novel method for controlling oxygen delivery to implanted cells.

According to one aspect of the invention, there is provided a method for controlling delivery of a gas to a cell implant, the method comprising the steps of (a) providing an electrolyzer, the electrolyzer having a variable gas output; (b) providing a cell capsule, the cell capsule comprising a cell chamber adapted to hold cells, wherein the cell capsule is fluidically coupled to the variable gas output of the electrolyzer; (c) measuring the total fluid pressure within the cell chamber; and (d) varying the variable gas output of the electrolyzer based on the measured total fluid pressure.

In a more detailed feature of the invention, the electrolyzer may be a water electrolyzer, and the gas may be oxygen.

In a more detailed feature of the invention, the measuring and varying steps may be performed automatically without requiring operator intervention.

In a more detailed feature of the invention, the measuring step may comprise using a total fluid pressure sensor.

In a more detailed feature of the invention, the total fluid pressure sensor may be disposed within the cell capsule.

In a more detailed feature of the invention, the total fluid pressure sensor may be disposed outside of the cell capsule.

In a more detailed feature of the invention, the water electrolyzer, the cell capsule, and the total fluid pressure sensor may be subcutaneously implanted in a subject.

In a more detailed feature of the invention, the varying step may comprise using a controller.

In a more detailed feature of the invention, the water electrolyzer, the cell capsule, the total fluid pressure sensor, and the controller may be subcutaneously implanted in a subject.

The present invention is also directed at a method for controlling oxygen concentration in a cell implant.

According to one aspect of the invention, a method for controlling oxygen concentration in a cell implant comprises the steps of (a) providing an electrochemical cell, the electrochemical cell being configured to operate alternatively in a water electrolyzer mode and in a fuel cell mode; (b) providing a cell capsule, the cell capsule comprising a cell chamber adapted to hold cells, wherein the cell capsule is fluidically coupled to the electrochemical cell; (c) measuring the total fluid pressure within the cell chamber; and (d) operating the electrochemical cell in one of the water electrolyzer mode and the fuel cell mode based on the measured total fluid pressure. For purposes of the present specification and claims, various relational terms like "top," "bottom," "proximal," "distal," "upper," "lower," "front," and "rear" may be used to describe the present invention when said invention is positioned in or viewed from a given orientation. It is to be understood that, by altering the orientation of the invention, certain relational terms may need to be adjusted accordingly.

Additional objects, as well as aspects, features and advantages, of the present invention will be set forth in part in the description which follows, and in part will be obvious from the description or may be learned by practice of the invention. In the description, reference is made to the accompanying drawings which form a part thereof and in which is shown by way of illustration various embodiments for practicing the invention. The embodiments will be described in sufficient detail to enable those skilled in the art to practice the invention, and it is to be understood that other embodiments may be utilized and that structural changes may be made without departing from the scope of the appended claims. The following detailed description is, therefore, not to be taken in a limiting sense, and the scope of the present invention is defined by the appended claims.

The accompanying drawings, which are hereby incorporated into and constitute a part of this specification, illustrate various embodiments of the invention and, together with the description, serve to explain the principles of the invention. These drawings are not necessarily drawn to scale, and certain components may have undersized and/or oversized dimensions for purposes of explication. In the drawings wherein like reference numeral represent like parts:.

In the present description <NUM> mmHg corresponds to <NUM> Pa.

The survival and function of implanted cell therapies depend critically on the availability of oxygen to support metabolism. While intravascular engraftment of cells or the integration of cells into well-vascularized capsules results in good exploitation of the recipient extant blood oxygen, there are practical limits to the density or thickness of cells transplanted due to diffusional limits of oxygen transport from the bulk to the mitochondria of all the cells. Because the oxygen tension (partial pressure, pO<NUM>) in the blood in the capillary environment of subcutaneous tissue (a useful implantation site) is relatively low (<<NUM> mmHg), there is an especial problem relating to device size, particularly for cells having high oxygen consumption rates and cluster morphologies, such as the islets of Langerhans.

A solution to the problem of cell survival, function and device size involves the provision of supplemental oxygen to the site of cell transplant, wherein the supplemental oxygen is sufficient to sustain the respiratory needs of all of the cells and allowing for increased cell density in the device. However, a fully implanted device preferably has no percutaneous vent of unused gas; therefore, oxygen delivered to the capsule is ideally terminal at the oxygen diffusion interface to the cells (i.e., dead-ended). Oxygen can be generated in a fully-implanted device by a number of methods, such as water electrolysis, as disclosed, for example, in <CIT>. As will be discussed further below, <FIG> is a simplified schematic representation of one embodiment of a system for controlled oxygen delivery to a cell implant, wherein the system involves the use of water electrolysis.

One-dimensional engineering modelling of cell capsules having a vascularized interface to recipient tissue on one face and supplemental oxygen delivery to the other face suggests that the delivered supplemental oxygen tension and the oxygen consumption rate of the cells should be matched to support the limits of hypoxic damage to or death of interior cells and hyperoxic damage to cells near the oxygen delivery face. Additionally, such modelling suggests that there is a range of cell density (% tissue, number of cell layers depth) that can be supported under any particular set of these input conditions (<FIG>). Due to extant nitrogen (<NUM> mmHg) and carbon dioxide (<NUM>-<NUM> mmHg) diffusion from the blood and the cell layers, there is typically higher-than-ambient pressure in the dead-ended gas compartment of the cell capsule in the steady-state, such that oxygen delivered has sufficient partial pressure to sustain diffusion to the cell layers.

Since the number of islets (reported in islet equivalents, or IE, averaging approximately <NUM> cells and a diameter of <NUM>) that comprise a curative dose (assumed here to be <NUM>,<NUM> IE) can be clinically evaluated, and the oxygen consumption rate (OCR) of those cells is known to be in the range of about <NUM>-<NUM> pmol-O<NUM>/IE/min, the relationship between cell density, delivered oxygen tension and capsule size is wellbounded. Nevertheless, the OCR of the cells at various depths may vary substantially during the normal rhythms of life, for example, as the capsule ages and densifies, and as environmental changes that may affect, for instance, blood pressure, blood flow, or subcutaneous temperature, ensue. Because the long-term viability of the islet cells depends critically on maintenance of oxygen tension in the range of, minimally, about <NUM> mmHg (e.g., to avoid cell death or loss of function and support glucose response) and, maximally, about <NUM> mmHg (e.g., to avoid hyperoxic damage by reactive oxygen species), there should be careful management of oxygen tension in the gas-fed cell capsule. Because the rate of oxygen delivery by an implanted oxygen generator can be varied - e.g., in a water electrolyzer by varying the applied current - there exists a way of programming the generator so as to maintain the oxygen tension within the appropriate limits. Therefore, in accordance with one embodiment of the invention, the total gas capsule pressure may be used for this purpose.

A special case of total gas pressure exists when a gas capsule and cell capsule are separated by a membrane of known oxygen diffusivity and the entire assembly is subjected to normal levels of respiratory (oxygen and carbon dioxide) and inert (i.e., nitrogen) gas partial pressures from the surrounding tissue and supplemental oxygen. Carbon dioxide partial pressures typically do not deviate very significantly in interstitial fluids; consequently, the gas capsule total pressure will be dominated by the approximately <NUM> mmHg extant nitrogen partial pressure and any additional pO<NUM> required to achieve the necessary diffusive oxygen flux across the membrane to the cell compartment. Water vapor pressure typically will be constant (~<NUM> mmHg) and carbon dioxide typically will be narrowly variable (e.g., about <NUM>-<NUM> mmHg), depending on the level of respiratory activity and the rate of diffusive clearance to host tissue. Calculations based on typical membrane materials and practical cell densities for a bioartificial pancreas application suggest that pO<NUM> maintained in the gas capsule should target about <NUM>-<NUM> mmHg, depending primarily on cell compartment(s) thickness/density and OCR. Thus, for any set of nominal conditions, the total gas compartment steady-state pressure may be about <NUM>-<NUM> mmHg (<NUM>-<NUM> psig), and in order to maintain the desired pO<NUM> conditions, the use of a gas pressure sensor in conjunction with the electrolyzer current controller constitutes a simple maintenance strategy. On-off or PID control algorithms may be utilized (see <NPL>)), and several pressure sensor technologies are amenable. Variations of the PID control algorithm may be used, such as the proportional-integral (PI) algorithm, where no derivative term is employed, or the proportional-derivative (PD) algorithm, where no integral term is employed. Closed-loop control is achieved by applying an algorithm to the difference between the observed total pressure and the total pressure setpoint. This difference (or "error") may be used in the algorithm to scale the change in the current setting or duty cycle (% "on" time) to attain the total pressure setpoint in the system. The benefits of PID control over on-off control include the ability to reach setpoint in a rapid and smooth approach, without "overshoot" or instabilities and with a minimum of hysteresis. An off-control is generally simpler to implement but intrinsically features a sawtooth periodicity due to the lack of intermediate current setting values. In either implementation, closed-loop control allows for relatively close management of oxygen partial pressure delivered to the gas capsule.

In the case of total gas capsule pressure closed-loop control, the sensor may be located in the oxygen delivery tube or inside the gas compartment of a multi-compartment cell container. By far, the most prevalent pressure sensing technology is based on a piezoresistive strain gauge (e.g., the IntraSense® piezoresistive MEMS sensor from Silicon Microstructures, Inc. , Milpitas, California). This pressure sensor type, like many other pressure sensor types, involves the placement of a transducing element onto a flexible diaphragm interposed between two sealed compartments, one being a reference and the other being a matrix of interest. When a pressure differential exists between the two compartments, the diaphragm deflects in response, and strain that occurs in the diaphragm material causes, in the case of the piezoresistive element, a change in resistance of one element in a Wheatstone bridge electrical circuit. (See <NPL>)). An operational amplifier circuit may be additionally configured to amplify the signal required to balance the bridge, thereby registering a signal corresponding to the pressure difference. The reference pressure can be various sealed or interfaced configurations for different types of sensors: sealed vacuum for absolute pressure transducers; ambient or atmospheric interface for gauge transducers; a second working interface for differential pressure transducers; and a confined gas at pressure for sealed pressure transducers.

Another pressure sensing technique is capacitive sensing, including membraneintegrated and interdigitated types. Similar to a piezoresistive sensor, a capacitive sensor relies on changes in an electrical circuit property upon deformation of a diaphragm in response to pressure differential. (See <NPL>)). In this case, one or both plates of a capacitor are built into a diaphragm, and separation of these plates causes a decrease in the capacitance value. This change manifests in the variation of a sensible dependent signal, such as the oscillation frequency of a circuit.

Additional information regarding pressure sensors may be found in <NPL>).

Due to the miniaturizability, stability and simplicity of a total gas pressure sensor, the present inventor believes that the use of a total gas pressure sensor, in concert with a control algorithm driving a current controller that, in turn, powers an implanted water electrolyzer that delivers oxygen to a cell compartment, is a particularly desirable way of managing oxygen delivery to a bioartificial pancreas device using cadaveric islets or stemcell derived beta cell clusters. The methods and component configurations described herein are similarly amenable and logically extensible to a variety of gas generation technologies, therapeutic (or otherwise useful) gas types, and cell or tissue therapeutic applications, or any combination thereof.

Thus, in a preferred embodiment, the present invention relates to a cell therapy device having elements for precise measurement and control of oxygen delivery to implanted cells and also relates to a method of optimally reacting to changes in oxygen demand in order to maintain long-term viability and function of the implanted cells.

Referring now to <FIG>, there is shown a simplified schematic representation of a first embodiment of a system for controlling oxygen delivery to a cell implant, the system being constructed according to the teachings of the present invention and being represented generally by reference numeral <NUM>. Details of system <NUM> that are discussed elsewhere in this application or that are not critical to an understanding of the invention may be omitted from <FIG> or the accompanying description herein or may be shown in <FIG> and/or described herein in a simplified manner.

System <NUM> may comprise a cell capsule <NUM>, a water electrolyzer <NUM>, a pressure sensor <NUM>, and a controller <NUM>.

Cell capsule <NUM> may comprise a conventional cell capsule or container adapted to contain implanted cells and/or tissues or may comprise a similarly suitable cell capsule or container. For example, but without limitation, cell capsule <NUM> may comprise a cell capsule or container of the type disclosed in any one or more of <CIT>, <CIT>, and <CIT>. In a preferred embodiment, cell capsule <NUM> may be a multi-compartment container of the type comprising a gas compartment <NUM> and two cell compartments <NUM> and <NUM>. Gas compartment <NUM> may be sandwiched between cell compartments <NUM> and <NUM> and may be separated therefrom by one or more membranes. Gas compartment <NUM> may be in gas communication with cell compartments <NUM> and <NUM>. For example, gas in gas compartment <NUM> may become soluble (i.e., dissolve) in the one or more membranes separating gas compartment <NUM> from cell compartments <NUM> and <NUM>; thereafter, said dissolved gas may enter cell compartment <NUM> and <NUM> from gas compartment <NUM> as a dissolved gas. Examples of cell capsules that may be suitable for use as cell capsule <NUM> may comprise, but are not limited to, cell containment system <NUM> of <CIT> and combined gas diffuser/cell capsule devices <NUM> and <NUM> of <CIT>.

Water electrolyzer <NUM> may comprise a conventional water electrolyzer or may comprise a similarly suitable water electrolyzer. For example, but without limitation, water electrolyzer <NUM> may comprise a water electrolyzer of the type disclosed in one or more of <CIT>, <CIT>, <CIT>, <CIT>, and <CIT>.

Water electrolyzer <NUM> may be used to electrochemically generate oxygen (and hydrogen) by splitting water, where the rate of oxygen generation is dictated by the rules of stoichiometry of the electrochemical reaction:.

<NUM><NUM>O → O<NUM> + <NUM>+ + <NUM> e-     (anode reaction).

<NUM>+ + <NUM> e- → <NUM><NUM>     (cathode reaction).

Therefore, the rate of oxygen generation is controlled by the rate of current flowing to water electrolyzer <NUM>. Controlling current may be performed using current source circuitry in the implanted device using electrical leads connected to the anode (+) and cathode (-) of water electrolyzer <NUM>. The source of water electrolyzed by water electrolyzer <NUM> may be water from tissue that is vicinal to the implantation site of water electrolyzer <NUM> or may be some other water source.

A length of tubing <NUM> or other similarly suitable gas conduit, which may be made of a substantially gas-impermeable material, may be used to fluidically couple an oxygen outlet <NUM> of water electrolyzer <NUM> with an oxygen inlet <NUM> of gas compartment <NUM> of cell capsule <NUM>. In this manner, oxygen outputted by water electrolyzer <NUM> may be delivered to cell capsule <NUM>. Hydrogen byproduct, which is also produced by electrolyzer <NUM>, may be delivered from an additional outlet (not shown) on water electrolyzer <NUM> towards the outside of a subject's body, either by a percutaneous tube or by diffusing into the blood and being expired at the lungs.

Pressure sensor <NUM> may comprise any sensor capable of sensing total fluid pressure, wherein said fluid may be in the form of a gaseous medium, a liquid medium, or a medium comprising both gas and liquid. For example, but without limitation, pressure sensor <NUM> may be a conventional piezoresistive-type pressure sensor or a conventional capacitivetype pressure sensor. In the present embodiment, pressure sensor <NUM> may be disposed within gas compartment <NUM> of cell capsule <NUM>. Because the fluid located within gas compartment <NUM> is likely to be substantially entirely a gaseous medium (as opposed to a liquid medium or a medium comprising significant amounts of both liquid and gas), pressure sensor <NUM> is likely to be tantamount to a gas pressure sensor.

Controller <NUM>, which may comprise a conventional microprocessor or a similarly suitable device, as well as a current source, such as a battery or the like, may be electrically connected with a wire <NUM> to pressure sensor <NUM> and may also be connected with a wire <NUM> to water electrolyzer <NUM>. As will be discussed further below, controller <NUM> may receive electrical signals from pressure sensor <NUM> relating to the total fluid pressure within gas compartment <NUM> and, based on such electrical signals and an algorithm, may control the operation of water electrolyzer <NUM>.

In use, the implanted cells that are contained within compartments <NUM> and <NUM> of cell capsule <NUM> preferably receive oxygen from water electrolyzer <NUM>. One or both of compartments <NUM> and <NUM> are preferably positioned sufficiently close to a subject's native vasculature to permit molecular exchange between the implanted cells and the subject's blood. In this manner, nutrients from the blood can be provided to the implanted cells, and secretions from the implanted cells can be provided to the subject for therapeutic effect. At the time of implant, the number of cells required for therapy may be determined as a function of the basal and stimulated needs (e.g., insulin needs) of the subject, and the cells may be loaded into appropriately-sized capsule(s) <NUM>. The capsule loading (cells per unit area of tissue interface) and the oxygen consumption rate (OCR) of the implanted cells may then be used to determine the preliminary oxygen dose (POD, standard cubic centimeters of oxygen per hour, scch) required. <MAT> where n(cells) is the total number of therapeutic cells required, OCR is the oxygen consumption rate in pmol-O<NUM>/IE/min, and n(islet) is the number of cells per islet equivalent (IE, typically <NUM> cells/islet). The factor <NUM> x <NUM>-<NUM> is the oxygen mass flow conversion factor between pmol/min and scch.

The preliminary current setpoint (iP) corresponding to the POD is calculated as: <MAT> wherein the factor <NUM> mA/scch is calculated from Faraday's Law as: <MAT> wherein Q is the flow rate in scch, F is Faraday's constant (<NUM>,<NUM> A-s/mol-e-), z is the transfer number of the electrochemical reaction (mol e-/mol-product; z = <NUM> for electrolytic oxygen production) and Vm is the molar gas volume at standard ambient conditions (<NUM>,<NUM> scc/mol-gas; temperature <NUM>° C, pressure <NUM> atmosphere).

As soon as the cells are loaded into capsule <NUM>, system <NUM> may establish and maintain a current setpoint using controller <NUM>, and the cells may be nourished in culture media (or a similar nutrient medium) during storage, transport and conditioning prior to implant. After implant, the cells may adjust to the nutrient availability inherent to the immediate environment, and, as such, the cells may remodel or suffer apoptosis. Preferably, capsule <NUM> has surface features that promote growth of plentiful new vascular structures near the cells, and capsule <NUM> may contain a membrane interposed between the cells and said surface features that prevents the penetration of antibodies into the interior of capsule <NUM> while still allowing facile transfer of hormones and smaller nutrient molecules. In this way, system <NUM> may provide a treatment for patients whose bodies are unable to provide sufficiently a key hormone or hormones secreted by the cells.

The signal from pressure sensor <NUM> may be utilized by controller <NUM> to inform changes to the current setpoint in order to best prolong the efficacy of the implanted cells, and thereby the duration of beneficial therapeutic effect, without imposing hardship to the patient, such as by the sudden or prolonged release of generated gas into the tissue stemming from overpressurization of or damage to water electrolyzer <NUM>, cell capsule <NUM>, or tubing <NUM>. Controller <NUM> may have the ability to measure, store and average over multiple time scales (from seconds to months) the voltage or current values corresponding to the pressure value transmitted by pressure sensor <NUM>. Controller <NUM> additionally may have the ability to control and verify the current applied to water electrolyzer <NUM>. Controller <NUM> preferably is programmed with an algorithm to respond to changes in observed pressure by changing the current setpoint, per the logic implied by the pressure trend examples and decision tree discussed below.

For example, referring now to <FIG>, there are shown graphs depicting various scenarios that may be encountered during the operation of system <NUM>. For example, in <FIG>, the implanted cells are behaving normally. As a result, the oxygen requirements of the implanted cells substantially match the amount of oxygen that is supplied to the implanted cells by water electrolyzer <NUM>. Consequently, the total gas pressure that is sensed by pressure sensor <NUM> stays fairly constant, and, accordingly, controller <NUM> causes the current at which water electrolyzer <NUM> operates to be kept constant. By contrast, in <FIG>, some of the implanted cells suffer cell distress or cell death. This temporarily causes the amount of oxygen supplied by water electrolyzer <NUM> to exceed the oxygen requirements of the implanted cells. Consequently, the total gas pressure that is sensed by pressure sensor <NUM> increases over time. To counter this increase, controller <NUM> causes the current at which water electrolyzer <NUM> operates to be reduced to an extent to cause the pressure to stabilize. In <FIG>, the oxygen consumption rate (OCR) of the implanted cells exceeds the amount of oxygen supplied by water electrolyzer <NUM>. This may be due, for example, to cell proliferation or may simply be due to an oxygen consumption that exceeds an initial projection. Because the oxygen consumption rate exceeds the rate at which oxygen is supplied to the implanted cells, the total pressure decreases over time. To counter this effect, controller <NUM> causes the current at which water electrolyzer <NUM> operates to be increased to an extent to cause the pressure to return to its initial level. <FIG> shows the effect of endocrine function. As can be seen, due to an increase in glucose concentration in a subject, there may be a transient increase in the rate of oxygen consumption. Consequently, this causes a corresponding decrease in the pressure sensed by pressure sensor <NUM> as the oxygen consumption rate outpaces the oxygen supply rate. However, because the increase in oxygen consumption is transient, the total pressure soon resumes its normal level - even without a change in the current at which water electrolyzer <NUM> operates. <FIG> shows a scenario that is similar to that of <FIG>, except that, in <FIG>, soon after the decrease in pressure is detected and before self-correction would otherwise occur, controller <NUM> causes an increase in the current at which water electrolyzer <NUM> is operated. This increase results in the pressure being restored to its initial level more quickly that it would have otherwise. Then, once the oxygen consumption rate returns to its initial level, controller <NUM> causes the current at which water electrolyzer <NUM> operates to be restored to its initial level. In <FIG>, where a fault condition occurs (e.g., fatal malfunction) and the pressure sensed by pressure sensor <NUM> drops to an unusually low level, controller <NUM> causes the current to water electrolyzer <NUM> to be shut off.

Referring now to <FIG>, there is shown a flowchart illustrating the operation of one embodiment of an algorithm employed by system <NUM> and, in particular, by controller <NUM>.

Controller <NUM> may, in this example, store running averages ("boxcar" or "first in - first out" buffers) of the implant gas pressure over the following timeframes for decisionmaking purposes: <NUM>-minute periods at <NUM>-second intervals (acute timeframe); <NUM> hour periods at <NUM>-minute intervals (metabolic timeframe); <NUM> day periods at <NUM>-hour intervals (cell-graft timeframe).

The acute timeframe may be utilized to capture sudden, abnormal changes in system pressure, which would be indicative of an acute situation or fault in the system. Controller <NUM> may appropriately elect to stop delivering gas to the cell capsule at this time (i.e., set the current setpoint to <NUM>) to prevent discomfort or other risks due to subcutaneous emphysema or other problems.

The metabolic timeframe may be utilized to capture changes in pressure which may occur normally as local or global cellular activity slows (i.e., during sleep or cold) or hastens (i.e., during post-prandial endocrine secretion activity, which may be glucosestimulated). Controller <NUM> may appropriately elect to increase oxygen production (i.e., set the current setpoint to a temporarily higher value) when pressure drops in this timeframe, so as to mitigate any risk of hypoxia in the cellular graft core. When pressure rises in the timeframe, controller <NUM> may appropriately elect to decrease oxygen production (i.e., set the current setpoint to a temporarily lower value) when pressure drops in this timeframe, so as to mitigate any risk of hyperoxic damage to cells near the gas compartment of the cell capsule. Alternatively, the oxygen system may be engineered such that its dead volume is sufficient enough that changes to current setpoint are not needed over this timeframe.

The cell-graft timeframe can be utilized to capture changes in pressure which may occur normally as the cells of the implant mature to a higher OCR condition or suffer damage from hypoxia or hyperoxia. Controller <NUM> may appropriately elect to increase oxygen production (i.e., set the current setpoint to a permanently higher value) when pressure drops in this timeframe, so as to mitigate any risk of hypoxia in the cellular graft core. When pressure rises in the timeframe, controller <NUM> may appropriately elect to decrease oxygen production (i.e., set the current setpoint to a permanently lower value) when pressure drops in this timeframe, so as to mitigate any risk of hyperoxic damage to cells near the gas compartment of the cell capsule. The cell-graft averaging buffer may optionally be erased upon any permanent change in current setpoint in this timeframe.

The total range of potential current setpoints may be limited to <NUM>% - <NUM>% of the iP determined at the time of implant from POD, and, if desired, no changes to the current setpoint may depart from these limits, except those dictated by an event in the acute timeframe.

In one embodiment of the invention, the entirety of system <NUM> may be implanted in a subject. In another embodiment of the invention, certain components of system <NUM> may be implanted in a subject and other components of system <NUM> may be external to a subject.

Although, in the present embodiment, pressure sensor <NUM> is disposed within gas compartment <NUM> of cell capsule <NUM>, it is to be understood that pressure sensor <NUM> need not be positioned within gas compartment <NUM> and, instead, may be located at a number of different locations within system <NUM>. This is because the total fluid pressure is fairly constant throughout cell capsule <NUM>, as well as within any fluid conduits coupled to cell capsule <NUM> and/or to water electrolyzer <NUM>. Various alternative embodiments illustrating this principle are discussed below.

Referring now to <FIG>, there is shown a simplified schematic representation of a second embodiment of a system for controlling oxygen delivery to a cell implant, the system being constructed according to the teachings of the present invention and being represented generally by reference numeral <NUM>. Details of system <NUM> that are discussed elsewhere in this application or that are not critical to an understanding of the invention may be omitted from <FIG> and/or the accompanying description herein or may be shown in <FIG> and/or described herein in a simplified manner.

System <NUM> may comprise a cell capsule <NUM>, a water electrolyzer <NUM>, a pressure sensor <NUM>, and a controller <NUM>. Cell capsule <NUM> may be identical to cell capsule <NUM>, water electrolyzer <NUM> may be identical to water electrolyzer <NUM>, pressure sensor <NUM> may be identical to pressure sensor <NUM>, and controller <NUM> may be identical to controller <NUM>. Wire <NUM> may electrically couple electrolyzer <NUM> and controller <NUM>, and wire <NUM> may electrically couple pressure sensor <NUM> and controller <NUM>.

System <NUM> may further comprise a tee-shaped tubing <NUM> of a substantially gas-impermeable material. A first end of tubing <NUM> may be fluidically coupled to cell capsule <NUM>, a second end of tubing <NUM> may be fluidically coupled to water electrolyzer <NUM>, and a third end of tubing <NUM> may be fluidically coupled to pressure sensor <NUM>.

System <NUM> may be operated in a manner analogous to that described above for system <NUM>.

Referring now to <FIG>, there is shown a simplified schematic representation of a third embodiment of a system for controlling oxygen delivery to a cell implant, the system being constructed according to the teachings of the present invention and being represented generally by reference numeral <NUM>. Details of system <NUM> that are discussed elsewhere in this application or that are not critical to an understanding of the invention may be omitted from <FIG> and/or the accompanying description herein or may be shown in <FIG> and/or described herein in a simplified manner.

System <NUM> may be similar in many respects to system <NUM>. One difference between the two systems may be that, whereas system <NUM> may comprise pressure sensor <NUM>, which may have a single fluid port, system <NUM> may comprise a pressure sensor <NUM>, which may have both a fluid inlet port and a fluid outlet port. Another difference between the two systems may be that, whereas system <NUM> may comprise tee-shaped tubing <NUM> fluidically interconnecting cell capsule <NUM>, water electrolyzer <NUM>, and pressure sensor <NUM>, system <NUM> may, instead, comprise a first length of tubing <NUM> and a second length of tubing <NUM>. First length of tubing <NUM> may fluidically interconnect water electrolyzer <NUM> and a pressure sensor <NUM>, and second length of tubing <NUM> may fluidically interconnect cell capsule <NUM> and pressure sensor <NUM>. Each of tubing <NUM> and tubing <NUM> may be made of a material similar to that of tubing <NUM>.

Referring now to <FIG>, there is shown a simplified schematic representation of a fourth embodiment of a system for controlling oxygen delivery to a cell implant, the system being constructed according to the teachings of the present invention and being represented generally by reference numeral <NUM>. Details of system <NUM> that are discussed elsewhere in this application or that are not critical to an understanding of the invention may be omitted from <FIG> and/or the accompanying description herein or may be shown in <FIG> and/or described herein in a simplified manner.

System <NUM> may be similar in many respects to system <NUM>. One difference between the two systems may be that, whereas system <NUM> may comprise electrolyzer <NUM>, which may have a single oxygen port, system <NUM> may comprise an electrolyzer <NUM>, which may have two oxygen ports. Another difference between the two systems may be that, whereas system <NUM> may comprise tee-shaped tubing <NUM> fluidically interconnecting cell capsule <NUM>, water electrolyzer <NUM>, and pressure sensor <NUM>, system <NUM> may, instead, comprise a first length of tubing <NUM> and a second length of tubing <NUM>. First length of tubing <NUM> may fluidically interconnect water electrolyzer <NUM> (at one of its two oxygen ports) and pressure sensor <NUM>, and second length of tubing <NUM> may fluidically interconnect cell capsule <NUM> and water electrolyzer <NUM> (at the other of its two oxygen ports). Each of tubing <NUM> and tubing <NUM> may be made of a material similar to that of tubing <NUM>.

Referring now to <FIG>, there is a simplified schematic representation of a fifth embodiment of a system for controlling oxygen delivery to a cell implant, the system being constructed according to the teachings of the present invention and being represented generally by reference numeral <NUM>. Details of system <NUM> that are discussed elsewhere in this application or that are not critical to an understanding of the invention may be omitted from <FIG> and/or the accompanying description herein or may be shown in <FIG> and/or described herein in a simplified manner.

System <NUM> may be similar in many respects to system <NUM>. One difference between the two systems may be that, whereas system <NUM> may comprise cell capsule <NUM>, which may have a single oxygen port, system <NUM> may comprise a cell capsule <NUM>, which may have two oxygen ports. Another difference between the two systems may be that, whereas system <NUM> may comprise tee-shaped tubing <NUM> fluidically interconnecting cell capsule <NUM>, water electrolyzer <NUM>, and pressure sensor <NUM>, system <NUM> may, instead, comprise a first length of tubing <NUM> and a second length of tubing <NUM>. First length of tubing <NUM> may fluidically interconnect water electrolyzer <NUM> and cell capsule <NUM> (at one of the two oxygen ports), and second length of tubing <NUM> may fluidically interconnect cell capsule <NUM> and water electrolyzer <NUM> (at the other of the two oxygen ports). Each of tubing <NUM> and tubing <NUM> may be made of a material similar to that of tubing <NUM>.

Referring now to <FIG>, there is a simplified schematic representation of a sixth embodiment of a system for controlling oxygen delivery to a cell implant, the system being constructed according to the teachings of the present invention and being represented generally by reference numeral <NUM>. Details of system <NUM> that are discussed elsewhere in this application or that are not critical to an understanding of the invention may be omitted from <FIG> and/or the accompanying description herein or may be shown in <FIG> and/or described herein in a simplified manner.

System <NUM> may be similar in many respects to system <NUM>. One difference between the two systems may be that, whereas system <NUM> may comprise a single cell capsule <NUM>, system <NUM> may comprise two cell capsules <NUM>-<NUM> and <NUM>-<NUM>. Each of cell capsules <NUM>-<NUM> and <NUM>-<NUM> may be identical to one another and may be identical to cell capsule <NUM>. Another difference between the two systems may be that, whereas system <NUM> may comprise tee-shaped tubing <NUM> fluidically interconnecting cell capsule <NUM>, water electrolyzer <NUM>, and pressure sensor <NUM>, system <NUM> may, instead, comprise a manifold <NUM> fluidically interconnecting water electrolyzer <NUM>, pressure sensor <NUM> and cell capsules <NUM>-<NUM> and <NUM>-<NUM>. Manifold <NUM>, which may be made of the same type of material as tubing <NUM>, may be shaped to branch into two legs <NUM>-<NUM> and <NUM>-<NUM> downstream of pressure sensor <NUM>.

Referring now to <FIG>, there is a simplified schematic representation of a seventh embodiment of a system for controlling oxygen delivery to a cell implant, the system being constructed according to the teachings of the present invention and being represented generally by reference numeral <NUM>. Details of system <NUM> that are discussed elsewhere in this application or that are not critical to an understanding of the invention may be omitted from <FIG> and/or the accompanying description herein or may be shown in <FIG> and/or described herein in a simplified manner.

System <NUM> may be similar in many respects to system <NUM>. One difference between the two systems may be that, whereas system <NUM> may comprise a single pressure sensor <NUM>, system <NUM> may comprise two pressure sensors <NUM>-<NUM> and <NUM>-<NUM>. Each of pressure sensors <NUM>-<NUM> and <NUM>-<NUM> may be identical to one another and may be identical to pressure sensor <NUM>. Pressure sensor <NUM>-<NUM> may be electrically coupled to controller <NUM> by a wire <NUM>-<NUM>, and pressure sensor <NUM>-<NUM> may be electrically coupled to controller <NUM> by a wire <NUM>-<NUM>. Another difference between the two systems may be that, whereas system <NUM> may comprise tee-shaped tubing <NUM> fluidically interconnecting cell capsule <NUM>, water electrolyzer <NUM>, and pressure sensor <NUM>, system <NUM> may, instead, comprise a manifold <NUM> fluidically interconnecting water electrolyzer <NUM>, pressure sensors <NUM>-<NUM> and <NUM>-<NUM>, and cell capsule <NUM>. Manifold <NUM>, which may be made of the same type of material as tubing <NUM>, may be shaped to have a constriction with an appropriately configured orifice in the length between the branches for pressure sensors <NUM>-<NUM> and <NUM>-<NUM>. In this manner, the difference in pressures read by pressure sensors <NUM>-<NUM> and <NUM>-<NUM> may be used to indicate the fluid flow, and the downstream sensor may be used to indicate total pressure.

System <NUM> may be operated in a manner similar to that described above for system <NUM>.

As discussed above, the various systems of the present invention are preferably configured so that the oxygen output from the water electrolyzer may be varied in response to the sensed total fluid pressure of the system. For example, this may result in the oxygen output from the water electrolyzer being increased when the sensed total fluid pressure of the system is below a desired level or may result in the oxygen output from the water electrolyzer being decreased when the sensed total fluid pressure of the system is above a desired level. However, there may be situations in which the sensed total fluid pressure of the system is higher than desired, and it may be desirable not only to decrease the oxygen output from the water electrolyzer but to actively remove oxygen from the system (i.e., at a rate faster than the metabolic consumption rate of the implanted cells). In accordance with one embodiment of the invention, this may be accomplished by providing a system that is capable of being alternatively operated in electrolyzer mode or in fuel cell mode. When such a system is operated in electrolyzer mode, the system outputs oxygen, and when such a system is operated in fuel cell mode, the system consumes oxygen. For example, the controller may be configured to operate in a forward (electrolytic) mode in order to develop positive pressure of oxygen by generating gas through the electrolytic reaction, and additionally may be configured to operate in a reverse (fuel cell) mode in order to reduce oxygen pressure by consuming the gas through the discharge of the oxygen and hydrogen in the system by the reverse fuel cell reaction:.

O<NUM> + <NUM>+ + <NUM> e- → <NUM><NUM>O (fuel cell cathode reaction).

<NUM><NUM> → <NUM>+ + <NUM> e- (fuel cell anode reaction).

The fuel cell mode may be governed by the electronic actuation of a transistor or switch, with an optional series resistor, in parallel with the electrolytic current control circuit, thereby allowing reverse current flow from the electrolyzer, and limited in time of actuation to achieve the desired reduced oxygen pressure. The fuel cell discharge may be used to enhance the rate of gas pressure reduction (i.e., in cases of overpressure during, for instance, diving or an implant system fault), so long as hydrogen gas is available in the open volumes of the electrolyzer cathode compartment, the hydrogen vent tubing and any attached hydrogen gas containing elements. An example of such a system is described below.

Referring now to <FIG> and <FIG>, there are shown simplified schematic representations of one embodiment of a system for controlling oxygen concentration within a cell implant, the system being constructed according to the teachings of the present invention and being represented generally by reference numeral <NUM>. Details of system <NUM> that are discussed elsewhere in this application or that are not critical to an understanding of the invention may be omitted from one or both of <FIG> and <FIG> and/or the accompanying description herein or may be shown in one or both of <FIG> and <FIG> and/or described herein in a simplified manner.

System <NUM> may be similar in many respects to system <NUM>. A principal difference between the two systems may be that, whereas system <NUM> may comprise controller <NUM>, which is configured to operate electrolyzer <NUM> only in an oxygen-producing mode, system <NUM> may instead comprise a controller <NUM>, which is configured to operate electrolyzer <NUM> either in an oxygen-producing mode (i.e., electrolyzer mode) or in an oxygen-consuming mode (i.e., fuel cell mode). More specifically, controller <NUM> may comprise a microprocessor or similarly suitable device <NUM> which may be connected to external pressure sensor <NUM>, an internal current controller <NUM> and electrical switches <NUM> and <NUM> enabled (i.e., turned on, such that the two connected wires are short-circuited) by signal wires. The single-pole, single-throw electrical switches used in this application may be any type that are able to create a closed and open circuit condition on the application of a suitable digital or analog signal, such as a mechanical relay (e.g., armature or reed relay) or a semiconductor device such as a solid state relay or field-effect transistor. Controller <NUM> may further comprise two circuits connected in parallel with the output to electrolyzer <NUM>. The electrolyzer mode circuit may include the current controller <NUM>, the implanted energy source (battery) <NUM> and the electrolyzer mode enable switch <NUM>, while the fuel cell mode circuit may include the fuel cell mode enable switch <NUM> and a current-limiting resistor <NUM>. As can be seen in <FIG>, the electrolyzer mode of operation may be actuated by turning on the electrolyzer mode switch <NUM> and turning off the fuel cell mode switch <NUM> using digital or analog output signals from the microprocessor <NUM>. The electrolyzer current setpoint may be established in the controller <NUM> by an analog or digital signal from the microprocessor <NUM> to the current controller <NUM>.

As can be seen in <FIG>, the fuel cell mode of operation may be actuated by turning off the electrolyzer mode switch <NUM> and turning on the fuel cell mode switch <NUM> using digital or analog output signals from the microprocessor <NUM>. A voltage will exist at the electrolyzer <NUM> after a period of electrolyzer mode operation due to the presence of oxygen and hydrogen products. This voltage, typically <NUM> to <NUM> volts, provides electrical potential required for current to flow spontaneously, and in a direction opposite to the electrolyzer mode, through the enabled fuel cell mode switch <NUM> and resistor <NUM>, causing a decrease in oxygen pressure, until hydrogen and/or oxygen activity at the electrolyzer electrochemical interfaces is depleted.

As can readily be appreciated by those skilled in the art of electronic circuitry, an analogous switching configuration can also be arranged by replacing the two single-pole, single-throw electronically-actuated switches with one single-pole double-throw electronically actuated switch, where the common to each throw is connected to the electrolyzer output and the microprocessor signal toggles between shorting the electrolyzer output to the current controller <NUM> (normally closed, electrolyzer mode) and shorting the electrolyzer output to the parallel circuit loop containing the current-limiting resistor <NUM>.

As can readily be appreciated, the arrangement of water electrolyzer <NUM>, total fluid pressure sensor <NUM> and cell capsule <NUM> in system <NUM> is merely illustrative; thus, the arrangement of these components may be modified along the lines of any of the systems described above.

Claim 1:
A system (<NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>) for controlling oxygen delivery to a cell implant, the system comprising:
a water electrolyzer (<NUM>, <NUM>, <NUM>), the water electrolyzer (<NUM>, <NUM>, <NUM>) being configured to generate gaseous oxygen;
a first cell capsule (<NUM>, <NUM>, <NUM>, <NUM>-<NUM>), the first cell capsule (<NUM>, <NUM>, <NUM>, <NUM>-<NUM>) comprising a cell compartment (<NUM>) adapted to hold cells and further comprising a gas compartment (<NUM>);
a first gas conduit (<NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>), the first gas conduit (<NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>) fluidically coupled to the water electrolyzer (<NUM>, <NUM>, <NUM>) and to the first cell capsule (<NUM>, <NUM>, <NUM>, <NUM>-<NUM>), whereby gaseous oxygen generated by the water electrolyzer (<NUM>, <NUM>, <NUM>) is delivered to the first cell capsule (<NUM>, <NUM>, <NUM>, <NUM>-<NUM>); and
a controller (<NUM>, <NUM>, <NUM>), the controller (<NUM>, <NUM>, <NUM>) being electrically coupled to the water electrolyzer (<NUM>, <NUM>, <NUM>), wherein the controller (<NUM>, <NUM>, <NUM>) is configured to control the water electrolyzer (<NUM>, <NUM>, <NUM>) ;
characterized in that
the system (<NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>) further comprises a first total fluid pressure sensor (<NUM>, <NUM>, <NUM>, <NUM>-<NUM>), wherein the water electrolyzer (<NUM>, <NUM>, <NUM>) is configured to output oxygen with a variable output, wherein the first total fluid pressure sensor (<NUM>, <NUM>, <NUM>, <NUM>-<NUM>) is placed so as to sense the total fluid pressure within the gas compartment (<NUM>) of the first cell capsule (<NUM>, <NUM>, <NUM>, <NUM>-<NUM>), wherein the controller (<NUM>, <NUM>, <NUM>) is also electrically coupled to the first total fluid pressure sensor (<NUM>, <NUM>, <NUM>, <NUM>-<NUM>), and wherein the controller (<NUM>, <NUM>, <NUM>) is configured to control the variable output of the water electrolyzer (<NUM>, <NUM>, <NUM>) based on one or more sensed total pressure readings from the first total fluid pressure sensor (<NUM>, <NUM>, <NUM>, <NUM>-<NUM>).