Millimeter-scale wireless implantable autonomous oxygenator platform and applications thereof

Abstract

An oxygenation system producing oxygen for therapeutic cells housed in an implanted or external system housing the therapeutic cells. The oxygenation system comprises a mm-scale oxygenator having at least one metal electrode; a miniaturized application-specific integrated circuit (ASIC) controlling an oxygen production by the oxygenator; a miniaturized communication unit; and a miniaturized power unit.

Description

MILLIMETER-SCALE WIRELESS IMPLANTABLE AUTONOMOUS OXYGENATORPLATFORM AND APPLICATIONS THEREOFSTATEMENT AS TO RIGHTS UNDER FEDERALLY-SPONSORED RESEARCH

[0001] This invention was made with government support under grant number FA8650-21-2- 7119 awarded by the Air Force Research Laboratory, and grant number AX000003 awarded by the National Institutes of Health. The government has certain rights in the invention.CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application Serial No. 63 / 618,138 (Atty Doc. No. 303US0), fded on January 5, 2024. The disclosure of the application is incorporated herein by reference.

[0002] This application claims priority to U.S. Provisional Patent Application Serial No. 63 / 741,644 (Atty Doc. No. 314US0), filed on January 3, 2025. The disclosure of the application is incorporated herein by reference.

[0003] This application is also a continuation-in-part of PCT / US23 / 19215 (Atty Doc. No. 268WO2) filed on Apr 20, 2023. The disclosure of the application is incorporated herein by reference.

[0004] This application is also a continuation-in-part of U.S. Patent Application Serial No. 18 / 287,671, U.S. Patent Application Serial No. 18 / 287,684, and U.S. Patent Application Serial No. 18 / 287,709, filed on October 20, 2023, which are U.S. national stage applications of PCT applications PCT / US22 / 25686 (Atty Doc. No. 266WO2), PCT / US22 / 25706(Atty Doc. No. 266WO22), and PCT / US22 / 25724 (Atty Doc. No. 266WO23) filed on April 21, 2022, respectively. The disclosures of each of these applications are also incorporated herein by reference.

[0005] This application is also a continuation-in-part of PCT application No. PCT / US23 / 36276 (Atty Doc. No. 276WO2) filed on October 30, 2023, which further claimed its priority to U.S. Provisional Patent Application Serial No. 63 / 420,219 filed on October 28, 2022. PCT application No. PCT / US23 / 36276 was also a continuation-in-part of PCT applications PCT / US22 / 25686, PCT / US22 / 25706, and PCT / US22 / 25724 filed on April 21, 2022, which further claimed priority of U.S. Provisional Patent Application Serial No. 63 / 177,806 filed onApril 21, 2021 . The disclosures of each of these applications are also incorporated herein by reference.

[0006] This application is also a continuation-in-part of PCT application No. PCT / US2024 / 047927 (Atty Doc. No. 297WO2), PCT / US2024 / 047934(Atty Doc. No. 297WO22), PCT / US2024 / 047943(Atty Doc. No. 297WO23), PCT / US2024 / 047951(Atty Doc. No. 297WO24), all of which are filed on September 23, 2024. The disclosures of each of these applications are also incorporated herein by reference.FIELD OF THE INVENTION

[0007] The present disclosure relates generally to the field of biomedical engineering, and more particularly to a millimeter-scale wireless implantable autonomous oxygenator platform, and applications of the same.BACKGROUND OF THE INVENTION

[0008] The background description provided herein is for the purpose of generally presenting the context of the present invention. The subject matter discussed in the background of the invention section should not be assumed to be prior art merely as a result of its mention in the background of the invention section. Similarly, a problem mentioned in the background of the invention section or associated with the subject matter of the background of the invention section should not be assumed to have been previously recognized in the prior art. The subject matter in the background of the invention section merely represents different approaches, which in and of themselves may also be inventions.

[0009] The transplantation of therapeutic cells, within semipermeable devices as a living pharmacy has the potential to treat a range of diseases such as endocrine disorders, autoimmune syndromes, cancers, and neurological degeneration. Cell-based therapeutics translation to humans requires high cell densities to enable miniaturized devices of therapeutic value. Studies have shown that encapsulated cells can survive at 6-10 k cells / mm3densities when implanted for treating type 1 diabetes and psoriasis. However, maintaining the potency of such densely packed therapeutic cells for extended duration is challenging due to a number of factors such as immune response from the host and inadequate availability of nutrients and dissolved oxygen. While immunoisolation and cell protection using encapsulating size-selective membranes or engineeredbiomaterials can partially address immunoreactivity, nutrient and oxygen insufficiency presents a critical challenge.

[0010] Oxygen has been regarded as the limiting factor supporting cell viability and potency. Due to the oxygen mass diffusion limit, in a native tissue each cell is within ca. 100 pm from a blood capillary to allow adequate oxygen supply. Transplanted exogenous cells or tissue require the formation of new blood vessels or supplemental oxygenation. Delay in vascularization limits the success of the transplantation as well as the transplanted cells’ function. Oxygen deficiency in the transplanted cells is caused by (1) insufficient oxygen tension at implantation site, (2) innate large oxygen consumption of cells (i.e., metabolic demand), (3) high cell density, (4) additional barriers to oxygen diffusion (i.e., membranes, or formation of encapsulating fibrotic tissue).

[0011] To address the hypoxic stress on transplanted cells, various strategies have been investigated to enhance exogenous oxygen delivery. Two major strategies employed to mitigate oxygen deficiency may be classified into active and passive methods. Active methods involve oxygen release through an externally controllable mechanism, e.g., delivery of gaseous oxygen to the transplanted cells (i.e., islet cells). Passive methods rely on gradual release of oxygen through unregulated or self-regulated mechanisms, e.g., engineered platforms to increase the oxygen exchange with the implantation environment or release of oxygen from metal peroxides. Though these approaches are able to support transplanted cells, they are limited in control of oxygen release, lifetime of available oxygen supply and limited supported cells’ density, e.g., pancreatic islet (10 k cells / mm3) and engineered cells (6 k cells / mm3).

[0012] Electrochemical water electrolysis for oxygen production is a promising approach for providing oxygen to cells. However, its demonstration in vivo has been limited due to improper materials selection geared toward efficient water splitting, the use of bulky and complex electronics for splitting water and limited power budget. Although electrocatalytic water splitting is widely accepted in renewable energy research, e.g., fuel cells, its application in tissue engineering has been limited due to the sluggish nature of water splitting in neutral environments. The pH-dependent nature of water’s redox reactions and its inherent thermodynamic stability further hinder electrochemical water decomposition in physiological environments, as they lack the necessary active species like H+and OH20. Additionally, neutral pH necessitates a higher overpotential, leading to increased power consumption and the potential risk of generating toxicbyproducts such as chlorine through chloride oxidation (E(C1) = 1 .771 V vs. RHE). Consequently, it is crucial to employ electrocatalysts that can effectively lower the energetic barrier while being biocompatible and highly selective for oxygen evolution reaction (OER) at neutral pH.

[0013] Previous exogenous oxygenation strategies have been bulky and had limited oxygen production or regulation.

[0014] Therefore, a heretofore unaddressed need exists in the art to address the aforementioned deficiencies and inadequacies.SUMMARY OF THE INVENTION

[0015] In light of the foregoing, this invention discloses an oxygenation system producing oxygen for therapeutic cells housed in an implanted or external system. The oxygenation system comprises a mm-scale oxygenator having at least one metal electrode; a miniaturized application-specific integrated circuit (ASIC) controlling an oxygen production by the oxygenator; a miniaturized communication unit; and a miniaturized power unit.

[0016] In one embodiment, the miniaturized ASIC is in sub-mm scale.

[0017] In one embodiment, the miniaturized communication unit is in sub-mm scale.

[0018] In one embodiment, the miniaturized communication unit is a low-power wireless communication unit.

[0019] In one embodiment, the miniaturized power unit comprises at least one battery having a diameter of 5 mm or less.

[0020] In one embodiment, the oxygenation system has a system diameter of 6 mm or less.

[0021] In one embodiment, the oxygenation system is configured to be administered to a subject using a minimum invasive method.

[0022] In one embodiment, the minimum invasive method comprises one of syringe injection and trocar delivery.

[0023] In one embodiment, the at least one metal electrode comprises a first electrode and a second electrode.

[0024] In one embodiment, one of the first and second electrodes comprises at least one catalyst for electrocatalytic oxygen evolution reaction (OER).

[0025] In one embodiment, the oxygenation system comprises a foldable substrate to which the mm-scale oxygenator, the miniaturized ASIC, and the miniaturized power unit are attached.

[0026] In another aspect of the invention, an implanted or external system housing therapeutic cells and integrated with an oxygenation system producing oxygen for the therapeutic cells comprises a cell containment subsystem having a house containing therapeutic cells and nutrition solution comprising water; and an oxygenation system, wherein the oxygenation system comprises a mm-scale autonomous oxygenator; and the oxygenator comprises at least one metal electrode located inside of the house.

[0027] In one embodiment, the oxygenation system further comprises a sub-mm applicationspecific integrated circuit (ASIC) controlling oxygen production.

[0028] In one embodiment, the oxygenation system further comprises a sub-mm communication unit.

[0029] In one embodiment, the sub-mm communication unit is a low-power wireless communication unit.

[0030] In one embodiment, the oxygenation system further comprises at least one battery.

[0031] In one embodiment, the at least one battery has a diameter of 5 mm or less.

[0032] In one embodiment, the at least one metal electrode comprises a first electrode and a second electrode.

[0033] In one embodiment, one of the first and second electrodes comprises at least one catalyst for electrocatalytic oxygen evolution reaction (OER).

[0034] In one embodiment, the one of the first and second electrodes for electrocatalytic OER comprises iridium oxides.

[0035] In one embodiment, the iridium oxides are converted from iridium metal wires.

[0036] In one embodiment, the first electrode is in contact with water exists in the nutrition solution in the house.

[0037] In one embodiment, the oxygenation system comprises a foldable substrate to which the mm-scale oxygenator, the ASIC, and the at least one battery are attached.

[0038] In one embodiment, the oxygenation system has a system diameter of 6 mm or less.BRIEF DESCRIPTION OF THE DRAWINGS

[0039] The accompanying drawings illustrate one or more embodiments of the invention andtogether with the written description, serve to explain the principles of the invention. Wherever possible, the same reference numbers are used throughout the drawings to refer to the same or like elements of an embodiment.

[0040] Fig. 1 illustrates a schematic diagram of a wire-based oxygenator having oxygengenerating catalysts.

[0041] Fig. 2 illustrates representative SEM images from low to high magnification of synthesized catalyst samples on wire electrodes.

[0042] Fig. 3 A illustrates a chart of linear sweep voltammetry (LSV) of wire electrode at 2 electrode system with different forms of counter electrodes.

[0043] Fig. 3B illustrates a chart of measured O2 concentration on chronoamperometry (CA) of a wire-based oxygenator at different potentials.

[0044] Fig. 3C illustrates charts of measured CL concentration and pH levels produced by the wire-based oxygenator at different potentials.

[0045] Fig. 3D illustrates a chart of measured O2 concentration on chronopotentiometry (CP) of a wire oxygenator.

[0046] Fig. 3E illustrates a chart reflecting long-term stability of wire oxygenators on CP at 20 uA in lx PBS.

[0047] Fig. 3F illustrates a chart reflecting LSV of modified SIROF wire electrodes at 3 electrode system and the corresponding onset overpotential of each sample.

[0048] Fig. 3G illustrates a chart reflecting representative LSV (n=3) for 1 cm of sputtered iridium oxide films (SIROF) on Pt / Ir wire and 3DFG@TiONW on Ti wire as working electrodes at 2 electrode system.

[0049] Fig. 4A illustrates charts reflecting XRD spectra of Ir-Pt wire oxidized by Li2COs and Na2CO3, respectively.

[0050] Fig. 4B illustrates SEM image of the nanoporous morphology of the Li2lrO3 crystal at 5k and 20k magnification.

[0051] Fig. 4C illustrates a chart of LSV of Ir / IrOx wires synthesized by chemical oxidation at 3 electrode system in PBS solution.

[0052] Fig. 5A illustrates a chart reflecting XRD spectra comparison of annealed and control SIROF.

[0053] Fig. 5B illustrates SEM image of SIROF (left) and SIROF annealed for Ih at 800 °C(right).

[0054] Fig. 6A illustrates a chart reflecting long-term stability of wire oxygenators on CP at 20 pA in lx PBS.

[0055] Fig. 6B illustrates SEM images of SIROF working electrode at Day 0 and Day 60.

[0056] Fig. 6C illustrates the measured 02 concentration level after 60 days of operation(13.0 ± 1.5 mg / L), with a picture on the right shows the setup for the measurement.

[0057] Fig. 6D illustrates charts reflecting comparison of LSV (n=3) for the SIROF wires at Day 0 and Day 60 (n = 3) and the corresponding onset overpotential of each sample.

[0058] Fig. 7 illustrates a schematic diagram of ecO2 for implantation.

[0059] Fig. 8 illustrates a diagram of 28nm CMOS system on mm-scale chip integrating the ecO2.

[0060] Fig. 9 illustrates an ecO2 block diagram.

[0061] Fig. 10 illustrates a lateral diagram of a battery empowering the ecO2 according to one embodiment of the invention.

[0062] Fig. 11 illustrates an assembly process of ecO2 with batteries.DETAILED DESCRIPTION OF THE INVENTION

[0063] The invention will now be described more fully hereinafter with reference to the accompanying drawings, in which exemplary embodiments of the invention are shown. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this invention will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art. Like reference numerals refer to like elements throughout.

[0064] The terms used in this specification generally have their ordinary meanings in the art, within the context of the invention, and in the specific context where each term is used. Certain terms that are used to describe the invention are discussed below, or elsewhere in the specification, to provide additional guidance to the practitioner regarding the description of the invention. For convenience, certain terms may be highlighted, for example using italics and / or quotation marks. The use of highlighting has no influence on the scope and meaning of a term; the scope and meaning of a term is the same, in the same context, whether or not it is highlighted. It will be appreciated that same thing can be said in more than one way.Consequently, alternative language and synonyms may be used for any one or more of the terms discussed herein, nor is any special significance to be placed upon whether or not a term is elaborated or discussed herein. Synonyms for certain terms are provided. A recital of one or more synonyms does not exclude the use of other synonyms. The use of examples anywhere in this specification including examples of any terms discussed herein is illustrative only, and in no way limits the scope and meaning of the invention or of any exemplified term. Likewise, the invention is not limited to various embodiments given in this specification.

[0065] One of ordinary skill in the art will appreciate that starting materials, biological materials, reagents, synthetic methods, purification methods, analytical methods, assay methods, and biological methods other than those specifically exemplified can be employed in the practice of the invention without resort to undue experimentation. All art-known functional equivalents, of any such materials and methods are intended to be included in this invention. The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention that in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention as defined by the appended claims.

[0066] Whenever a range is given in the specification, for example, a temperature range, a time range, or a composition or concentration range, all intermediate ranges and subranges, as well as all individual values included in the ranges given are intended to be included in the invention. It will be understood that any subranges or individual values in a range or subrange that are included in the description herein can be excluded from the claims herein.

[0067] It will be understood that, as used in the description herein and throughout the claims that follow, the meaning of “a”, “an”, and “the” includes plural reference unless the context clearly dictates otherwise. Thus, for example, reference to “a cell” includes a plurality of such cells and equivalents thereof known to those skilled in the art. As well, the terms “a” (or “an”), “one or more” and “at least one” can be used interchangeably herein. It is also to be noted that the terms “comprising”, “including”, and “having” can be used interchangeably.

[0068] It will be understood that when an element is referred to as being “on”, “attached” to, “connected” to, “coupled” with, “contacting”, etc., another element, it can be directly on, attached to, connected to, coupled with or contacting the other element or intervening elements may also be present. In contrast, when an element is referred to as being, for example, “directly on”, “directly attached” to, “directly connected” to, “directly coupled” with or “directly contacting” another element, there are no intervening elements present. It will also be appreciated by those of skill in the art that references to a structure or feature that is disposed “adjacent” another feature may have portions that overlap or underlie the adjacent feature.

[0069] It will be understood that, although the terms first, second, third etc. may be used herein to describe various elements, components, regions, layers and / or sections, these elements, components, regions, layers and / or sections should not be limited by these terms. These terms are only used to distinguish one element, component, region, layer or section from another element, component, region, layer or section. Thus, a first element, component, region, layer or section discussed below could be termed a second element, component, region, layer or section without departing from the teachings of the invention.

[0070] Furthermore, relative terms, such as “lower” or “bottom” and “upper” or “top,” may be used herein to describe one element’s relationship to another element as illustrated in the figures. It will be understood that relative terms are intended to encompass different orientations of the device in addition to the orientation depicted in the figures. For example, if the device in one of the figures is turned over, elements described as being on the “lower” side of other elements would then be oriented on “upper” sides of the other elements. The exemplary term “lower”, can therefore, encompasses both an orientation of “lower” and “upper,” depending of the particular orientation of the figure. Similarly, if the device in one of the figures is turned over, elements described as “below” or “beneath” other elements would then be oriented “above” the other elements. The exemplary terms “below” or “beneath” can, therefore, encompass both an orientation of above and below.

[0071] It will be further understood that the terms “comprises” and / or “comprising”, or “includes” and / or “including”, or “has” and / or “having”, or “carry” and / or “carrying”, or “contain” and / or “containing”, or “involve” and / or “involving”, “characterized by”, and the like are to be open-ended, i.e., to mean including but not limited to. When used in this disclosure, they specify the presence of stated features, regions, integers, steps, operations, elements, and / orcomponents, but do not preclude the presence or addition of one or more other features, regions, integers, steps, operations, elements, components, and / or groups thereof.

[0072] Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the relevant art and the invention, and will not be interpreted in an idealized or overly formal sense unless expressly so defined herein.

[0073] As used in the disclosure, “around”, “about”, “approximately” or “substantially” shall generally mean within 20 percent, preferably within 10 percent, and more preferably within 5 percent of a given value or range. Numerical quantities given herein are approximate, meaning that the term “around”, “about”, “approximately” or “substantially” can be inferred if not expressly stated.

[0074] As used in the disclosure, the phrase “at least one of A, B, and C” should be construed to mean a logical (A or B or C), using a non-exclusive logical OR. As used herein, the term “and / or” includes any and all combinations of one or more of the associated listed items.

[0075] As used in the disclosure, the term “implantable” refers to an ability of a device to be positioned at a location within a body of a user, such as subcutaneously, within a body cavity, or etc. Furthermore, the terms “implantation” and “implanted” refer to the positioning of a device at a location within a body of a user, such as subcutaneously, within a body cavity, or etc.

[0076] As used in the disclosure, the term “wearable” refers to articles, adornments or items designed to be worn by a user, incorporated into another item worn by a user, act as an orthosis for the user, or interfacing with the contours of a user's body.

[0077] As used in the disclosure, “biocompatible” material is a material that is compatible with living tissue or a living system by not being toxic or injurious and not causing immunological rejection.

[0078] As used in the disclosure, “therapeutics” and “therapeutic agent” refer to any substance that provides therapeutic effects to a disease or symptom related thereto. In certain embodiments, a therapeutic agent refers to a substance that provides therapeutic effects to any diseases or biological or physiological responses to the diseases.

[0079] As used in the disclosure, the term “therapy” refers to any protocol, method, and / oragent that can be used in the management, treatment, and / or amelioration of a given disease, or a symptom related thereto. In certain embodiments, the terms “therapies” and “therapy” refer to a biological therapy, supportive therapy, and / or other therapies known to one of skill in the art, such as medical personnel, useful in the management or treatment of a given disease, or symptom related thereto.

[0080] As used in the disclosure, “treat”, “treatment”, and “treating” refer to the reduction or amelioration of the progression, severity, and / or duration of a given disease resulting from the administration of one or more therapies (including, but not limited to, the administration of microspheres disclosed herein). In certain embodiments, the terms refer to the reduction of pain associated with one or more diseases or conditions.

[0081] As used in the disclosure, “engineered cell(s)” refers herein to cells having been engineered, e.g., by the introduction of an exogenous nucleic acid sequence or specific alteration of an endogenous gene sequence. An exogenous nucleic acid sequence that is introduced may comprise a wild type sequence of any species that may be modified. An engineered cell may comprise genetic modifications such as one or more mutations, insertions and / or deletions in an endogenous gene and / or insertion of an exogenous nucleic acid (e g., a genetic construct) in the genome. An engineered cell may refer to a cell in isolation or in culture. Engineered cells may be “transduced cells” wherein the cells have been infected with e.g., an engineered virus. For example, a retroviral vector may be used, such as described in the examples, but other suitable viral vectors may also be contemplated such as lentiviruses. Non-viral methods may also be used, such as transfections or electroporation of DNA vectors. DNA vectors that may be used are transposon vectors. Engineered cells may thus also be “stably transfected cells” or “transiently transfected cells”. Transfection refers to non-viral methods to transfer DNA (or RNA) to cells such that a gene is expressed. Transfection methods are widely known in the art, such as calcium phosphate transfection, PEG transfection, and liposomal or lipoplex transfection of nucleic acids. Such a transfection may be transient but may also be a stable transfection wherein cells can be selected that have the gene construct integrated in their genome.

[0082] As used in the disclosure, “low-power wireless communication” refers herein to a class of wireless technologies that use minimal power to transmit data, including Low-Power Wide-Area (LPWA), Bluetooth low energy (BLE), ANT, IEEE 802.11 ah. a “low-power wireless communication unit” refers to a component unit performing the low-power wirelesscommunication. Particularly, the “low-power wireless communication unit” is preferred to be Bluetooth low energy wireless communication unit.

[0083] As used in the disclosure, “mm-scale” refers herein to a size, length, or dimensional measurement that is expressed in millimeters (mm). It is used to describe objects, features, or phenomena that range in the order of millimeters. In engineering, mm-scale refers to precision components or manufacturing tolerances.

[0084] As used in the disclosure, “sub mm-scale” refers herein to a size, length, or dimensional measurement that is smaller than one millimeter (< 1 mm). It typically ranges from fractions of a millimeter down to micrometers.

[0085] As used in the disclosure, “miniaturized” refers herein to the process or result of reducing the size, dimensions, or scale of an object, device, or system while retaining its functionality, performance, or key features. A miniaturized unit or system is to describe a unit or a system that is downsized for improved efficiency, portability, or integration. Particularly, the “miniaturized unit” is preferred to be in mm scale or sub-mm scale.

[0086] The present invention describes a highly controlled, on demand electrocatalytic onsite oxygenator (ecCh) platform designed to safely and efficiently support implanted therapeutic cells. Capitalizing on its unique catalytic properties, stability, patternability and biocompatibility, the present invention employed a nanostructured sputtered iridium oxide film (SIROF) to enhance the kinetics of OER and reduce the energetic cost to produce oxygen. Detailed engineering of the ecCh geometry resulted with precise control over the distribution of generated oxygen.

[0087] In one embodiment, in vitro experiments assessed the platform’s ability to sustain cell viability while maintaining therapeutic peptide secretion at a high-cell density (60k cells / mm3) under hypoxic conditions (1% O2) up-to 3 weeks.

[0088] In one embodiment, ecO2 effectiveness was subcutaneously tested in vivo (rat) for 10 days, showing its promise as a tool for cell-based therapeutic interventions, and providing support for biomedical engineering applications, e.g., transplanted cells to treat diabetes or cancer. In one embodiment, the ecO2 is adapted to provide treatment for one or more of obesity, diabetes, HIV, sleep diseases and entrainment and etc.

[0089] In one embodiment, the present invention provides an ultra small oxygenator to be syringe implanted into a patient, which can be accomplished by professionals within a short timeperiod, e.g. a few minutes.

[0090] In one embodiment, the oxygenator has a size of approximately 5x5 mm, and up to 10 mm long. In one embodiment, the oxygenator has a size of approximately 3x3 mm. In one embodiment, the oxygenator has a size of approximately 4x4 mm. In one embodiment, the oxygenator has a size of approximately 6x6 mm. In one embodiment, the oxygenator has a size of approximately 7x7 mm.

[0091] In one embodiment, the oxygenator has a length between about 2-4 mm. In one embodiment, the oxygenator has a length between about 4-6 mm. In one embodiment, the oxygenator has a length between about 6-8 mm. In one embodiment, the oxygenator has a length between about 8-10 mm. In one embodiment, the oxygenator has a length between about 10-12 mm. In one embodiment, the oxygenator has a length between about 12-14 mm. In one embodiment, the oxygenator has a length between about 14-16 mm. In one embodiment, the oxygenator has a length between about 16-18 mm. In one embodiment, the oxygenator has a length between about 18-20 mm. In one embodiment, the oxygenator has a length between about 20-25 mm. In one embodiment, the oxygenator has a length between about 25-30 mm.

[0092] In one embodiment, the present invention includes a low-cost oxygenation platform with a custom application specific integrated circuit (ASIC) that powers and operates the oxygenation device. In one embodiment, the present invention incorporates commercial off-the- shelf batteries, e.g. small watch batteries, to power the device for approximately 18-34 months without the need for replacement or removal. In one embodiment, the present invention uses customized batteries having a mm-scale size to power the ecO2 device.

[0093] In one embodiment, the present invention includes an inductive coil and / or low- energy wireless communication unit (e.g. Bluetooth Low energy unit) to facilitate a wireless connection to other devices. Due to the simple circuit, the use of commercial off-the-shelf batteries, and the reduction in the price of using wires for the oxygenator, the oxygenation platform of the present invention is in an ultra-small implantable form and last for years without the need for replacement or removal.

[0094] In one embodiment, the device includes a small regulator or feedback controller to ensure proper oxygen generation on a chip powered by primary batteries.

[0095] In one embodiment, the oxygenation platform is a mm-scale device, with a sub-mm scale ASIC.

[0096] In one embodiment, the present invention discloses a mm-scale fully integrated oxygenation platform that can be deployed with existing and future cell therapies to improve the therapy’s efficacy 10 to 100 fold, while reducing patient burden, total cost of medical treatment, and time to deploy.

[0097] The present invention discloses an ecO2 device having an extremely small form factor and an ultra-long battery life time, which prevents frequent replacement of batteries, and thus enables a user visit medical professionals less frequent, e.g., only once every few years, to receives a short medical treatment, e.g. a five minute minor surgery. Due to the fully contained power and electronics as well as low power consumption, the present invention obviates the need for an external charger or a wearable device to provide any external power source.Embodiment 1

[0098] The present invention describes a wire-based catalytic oxy gen-generating platform in mm-scale or sub mm-scale sizes, and its utilization in tissue engineering, as well as advances and potential applications of the wire-based catalytic oxygen-generating platform. A three- dimensional wire-based oxy gen-generating device is necessary to support large numbers of cells due to the poor diffusivity of oxygen in aqueous media.

[0099] In certain embodiments, the wire-based oxygenation assembly includes catalyst- coated wires as working electrodes and wires serving as counter electrodes.

[0100] In certain embodiments, wire-based oxygenators have a streamlined manufacturing process that can be readily tuned for material modifications.

[0101] In certain embodiments, the large interfacial area of a wire-based oxygenator having a 3D configuration provides a greater area for catalyst loading and demonstrates a better oxygen distribution profile than 2D oxygenator systems.

[0102] In certain embodiments, electrochemical tests have shown that wire-based oxygenator assemblies operate efficiently at lower potentials, comparing to fabricated thin film oxygenators, which provide the advantages of lower power consumption and avoiding competing side reactions, e.g. byproducts productions.

[0103] In certain embodiments, the wire-based oxygenator has wires coated with catalytic materials. In certain embodiments, the catalytic materials include iridium oxide, 3D fuzzy graphene, selective transition metal oxides, etc.

[0104] In certain embodiments, the wires coated with catalytic materials do not require any patterning of deposited material, which makes the manufacturing process significantly faster and less complex. In particular, it allows the ease of fabrication and control over the nanomorphology of the electrocatalyst by using straightforward synthesis approaches including electrochemical, hydrothermal, as well as sol-gel synthesis.

[0105] In certain embodiments, the synthesis approaches include other methods commonly used in the field.

[0106] In certain embodiments, the wire-based oxygenator system maintains stability and compliance at higher temperatures than conventional polymeric flexible substrates, which allows the implementation of annealing and hydrothermal processes to enhance catalyst performance.

[0107] In certain embodiments, the shape, size, and other configurations, e.g. number of turns, of the wire-based oxygenator are customizable. The flexibility of a wire allows it to assume a variety of form factors, which can be readily customized to oxygenate regions of varying shape and size.

[0108] In certain embodiments, working-counter electrode configurations include a wirewire, a wire-coil, a coil-wire, or a coil-coil geometry form. In certain embodiments, the workingcounter electrode configuration of the oxygenator is customizable for maximizing the longevity and / or performance of the oxygenator.

[0109] The present invention provides a mm-scale or sub mm-scale oxygenator having a coiled wire geometry. In certain embodiments, the oxygenator has a coiled wire geometry having a diameter between 1-2 mm. In certain embodiments, the oxygenator has a coiled wire geometry having a diameter between 2-3 mm. In certain embodiments, the oxygenator has a coiled wire geometry having a diameter between 3-4 mm. In certain embodiments, the oxygenator has a coiled wire geometry having a diameter between 4-5 mm. In certain embodiments, the oxygenator has a coiled wire geometry having a diameter between 5-6 mm. In certain embodiments, the oxygenator has a coiled wire geometry having a diameter between 6-7 mm. In certain embodiments, the oxygenator has a coiled wire geometry having a diameter between 7-8 mm. In certain embodiments, the oxygenator has a coiled wire geometry having a diameter between 8-9 mm. In certain embodiments, the oxygenator has a coiled wire geometry having a diameter between 9-10 mm.

[0110] In certain embodiments, the oxygenator has a straight wire geometry having a length less than about 1.0 cm. In certain embodiments, the oxygenator has a straight wire geometry having a length between about 1.0 cm - 2.0 cm. In certain embodiments, the oxygenator has a straight wire geometry having a length between about 2.0 cm - 2.5 cm. In certain embodiments, the oxygenator has a straight wire geometry having a length between about 2.5 cm - 3.0 cm. In certain embodiments, the oxygenator has a straight wire geometry having a length between about 3.0 cm - 3.5 cm. In certain embodiments, the oxygenator has a straight wire geometry having a length between about 3.5 cm - 4.0 cm. In certain embodiments, the oxygenator has a straight wire geometry having a length between about 4.5 cm - 4.5 cm. In certain embodiments, the oxygenator has a straight wire geometry having a length between about 4.5 cm - 5.0 cm. In certain embodiments, the oxygenator has a straight wire geometry having a length between about 5.0 cm - 5.5 cm. In certain embodiments, the oxygenator has a straight wire geometry having a length between about 5.5 cm - 6.0 cm. In certain embodiments, the oxygenator has a straight wire geometry having a length between about 6.0 cm - 6.5 cm. In certain embodiments, the oxygenator has a straight wire geometry having a length between about 6.5 cm - 7.0 cm.

[0111] In certain embodiments, the oxygenator has a coiled wire geometry having 3 turns. In certain embodiments, the oxygenator has a coiled wire geometry having 4 turns. In certain embodiments, the oxygenator has a coiled wire geometry having 5 turns. In certain embodiments, the oxygenator has a coiled wire geometry having 6 turns. In certain embodiments, the oxygenator has a coiled wire geometry having 7 turns. In certain embodiments, the oxygenator has a coiled wire geometry having 8 turns. In certain embodiments, the oxygenator has a coiled wire geometry having 9 turns. In certain embodiments, the oxygenator has a coiled wire geometry having 10 turns. In certain embodiments, the oxygenator has a coiled wire geometry having 11 turns. In certain embodiments, the oxygenator has a coiled wire geometry having 12 turns. In certain embodiments, the oxygenator has a coiled wire geometry having 13 turns. In certain embodiments, the oxygenator has a coiled wire geometry having 14 turns. In certain embodiments, the oxygenator has a coiled wire geometry having 15 turns.

[0112] In certain embodiments, the mm-scale or sub mm-scale wire-based oxygenator is operated in association with a mm-scale or sub mm-scale biomedical device housing natural cells or engineered cells. In certain embodiments, the biomedical device is implantable into a livingsubject via a minimal invasive delivery method due to its mm-scale or sub mm-scale size. In certain embodiments, the biomedical device is a porous, insulating housing and covered by an immunoisolation membrane while allowing gas and nutrient exchange between the inside of the biomedical device and surrounding environment. In certain embodiments, an insulating cap for the cell housing contains electronics for device operation.

[0113] In certain embodiments, the working and counter electrodes are attached to the biomedical device and extend into the cell housing when capped.

[0114] In certain embodiments, an insulating scaffold holds the working and counter electrodes in a desired position to achieve optimal oxygen supply over the biomedical device volume and prevent shorting of the electrodes.

[0115] In certain embodiments, the biomedical device is assembled by loading the cell housing with living cells and then attached to the insulating cap containing the electronics, scaffold, and electrodes of the oxygenator in the desired orientation. In certain embodiments, the cell housing, the insulating cap containing the electronics, scaffold, and electrodes of the oxygenator are assembled via a snap-fit mechanism.

[0116] The ease of manufacturing and diverse, customizable form factors of wire-based oxygenator allows the creation of stable bio interfaces, which makes the wire-based oxygenator capable of providing sufficient oxygen to support tissue functions for a variety of applications.

[0117] Fig. 1 shows a schematic illustration of a mm-scale or sub mm-scale wire-based oxygenator incorporating oxy gen-generating catalysts. In certain embodiments, the wire-based oxygenator includes a scaffold 15, a working electrode (anode) 11, and a counter electrode (cathode) 13.

[0118] In certain embodiments, the scaffold is made of one or more insulating materials. In certain embodiments, the working electrode has one or more electrocatalysts for water oxidation. In certain embodiments, the electrocatalysts are biocompatible. In certain embodiments, the electrocatalysts include sputtered iridium oxide fdm (SIROF), 3-dimensional Fuzzy Graphene (3DFG), Titanium Oxide Nano Wires (TiONW), and etc.

[0119] In certain embodiments, the electrocatalyst is nanostructured. In certain embodiments, as shown in the green dash inset, the working electrode can be fabricated into various forms on its surface according to the needs of the biomedical device, e.g. uniform distribution of the oxygen, maximum production of the oxygen, and etc. In certain embodiments, the surface of theworking electrode is in a serrated form. In certain embodiments, the surface of the working electrode is in an arrow-feathered form.

[0120] In certain embodiments, the working electrode is a straight wire configuration while the counter electrode is in a coiled wire configuration. In certain embodiments, the working electrode is a coiled wire configuration while the counter electrode is in a straight wire configuration. In certain embodiments, both of the working electrode and the counter electrode are in a coiled wire configuration. In certain embodiments, both of the working electrode and the counter electrode are in a straight wire configuration.

[0121] In certain embodiments, the length of the straight form electrode is customizable according to the need of the oxygenator and the biomedical device housing the cells.

[0122] In certain embodiments, the diameter, the number of turns, and length of the coiled form electrode is customizable according to the need of the oxygenator and the biomedical device housing the cells.

[0123] In one embodiment, the present invention provides an ultra-small oxygenator to be syringe implanted into a patient, which can be accomplished by professionals within a short time, e.g. a few minutes. In one embodiment, the oxygenator has a size of approximately 5 x 5 mm, and up to 10 mm long.

[0124] In certain embodiments, the present invention includes a low-cost oxygenation platform with a custom application specific integrated circuit (ASIC) that powers and operates the oxygenation device. In certain embodiments, the present invention incorporates commercial off-the-shelf batteries, e g. small watch batteries, to power the device for approximately 18-34 months without the need for replacement or removal.

[0125] In certain embodiments, the batteries are rechargeable. In certain embodiments, the batteries are rechargeable via wireless power transmission.

[0126] In certain embodiments, the present invention includes an inductive coil and / or Bluetooth Low energy facilitate a wireless connection to other devices. Due to the simple circuit, the use of commercial off-the-shelf batteries, and the reduction in the price of using wires for the oxygenator, the oxygenation platform of the present invention is in an ultra-small implantable form factor and last for years without the need for replacement or removal.

[0127] In certain embodiments, the present invention discloses a mm-scale fully integrated oxygenation platform that can be deployed with existing and future cell therapies to improve theefficacy 10 to 100-fold, reducing patient burden, total cost of medical treatment, and time to deploy. In one embodiment, the device includes a small regulator or feedback controller to ensure proper oxygen generation on a chip powered by primary batteries.

[0128] The extremely small form factor and ultra long battery lifetime of the present invention enable a user visit medical professionals less frequent, e.g., only once every few years, to receives a short medical treatment, e.g. a five minute minor surgery. Due to the fully contained power and electronics as well as low power consumption, there is no need for an external charger or wearable device.

[0129] Fig. 2 shows representative SEM images from low-mag to high-mag for synthesized samples on wire electrodes (scale bar: 100 um, 20 um, and 1 um). In particular, the upper panel shows a SEM image of a working electrode having sputtered Iridium Oxide Films (SIROF) deposited on Pt / Ir wires. The middle panel shows a SEM image of a working electrode having titanium oxide nano wires (TiONW) deposited on titanium (Ti) wire. The lower panel shows a SEM image of a working electrode having 3-dimensional Fuzzy Graphene (3DFG) deposited on TiONW wire.

[0130] Figs. 3A-G show working status of oxygenators of various configurations and / or materials.

[0131] Fig. 3A shows a charts of representative linear sweep voltammetry (LSV) of wire electrode at 2 electrode system with different forms of counter electrodes. In particular, the tested counter electrodes have 4 turns, 8 turns, 12 turns, and 11 turns with Pt Black deposited. Fig. 3B shows the measured O2 concentration on chronoamperometry (CA) of a wire oxygenator. In particular, when the potential is 0.6 V and above, O2 levels exceeded 40 Torr, which is necessary for the cells maintain functionality. Fig. 3C shows pH levels and production of byproducts Ch at different potentials. As it can be seen, when the potential reaches 0.9 V, the production of Ch significantly increases.

[0132] Fig. 3D shows a chart reflecting measured O2 concentration on chronopotentiometry (CP) of a wire oxygenator having a straight form working electrode and a coiled formed counter electrode. When the current reaches above 10 uA, O2 levels exceeded 40 Torr, which is necessary for the cells maintaining their functionality.

[0133] Fig. 3E shows a chart reflecting long-term stability of wire-based oxygenators on CP at 20 uA in lx PBS.

[0134] Fig. 3F shows a chart reflecting LSV of modified SIROF wire electrodes of 3 electrode system and the corresponding onset overpotential of each sample. In particular, the light green represents electrode of bare Pt / Ir wire, and the light blue represents SIROF decorated Pt / Ir wire. The orange represents Mn and hydroxide doped SIROF, and the dark green represents Mn and phosphate doped SIROF. The chart on the right shows that the SIROF decorated Pt / Ir wire has the highest onset overpotential, and the Mn and phosphate doped SIROF has the lowest onset overpotential.

[0135] Fig. 3G shows a chart reflecting representative LSV (n=3) for 1 cm of SIROF decorated Pt / Ir wire as working electrodes at 2 electrode system and 3DFG decorated TiONW on Ti wire as working electrodes at 2 electrode system.

[0136] Fig. 4A shows XRD spectra of Ir-Pt wire oxidized by Li2CO3(right) and Na2CO3(left), respectively. The XRD spectra indicates that the composition of the oxide to be Li2CO3 crystal (right) and Na2CO3 crystal (left), respectively.

[0137] Fig. 4B shows SEM images of the nanoporous morphology of the Li2lrO3 crystal at 5k and 20k magnification.

[0138] Fig. 4C shows a chart reflecting LSV of Ir / IrOx wires synthesized by chemical oxidation at 3 electrode system in PBS solution. As shown, both Li2lr03 and Na2CO3 wires show lower overpotential and higher current. Working electrode is Ir / IrOx wires (Orange represents Li2lrO3 / Ir wire, red represents Na2CO3 / Ir wire) Counter electrode is Pt; Reference electrode is Ag / AgCl.

[0139] Fig. 5A shows XRD spectra comparison of annealed and control SIROF. The annealed sample is significantly more crystalline, evidenced by the increase in peak intensity and sharpness. Fig. 5B is a SEM image of SIROF (left) and SIROF annealed for 1 hour at 800 °C (right). The grains observed are significantly less dendritic and larger, indicating a more crystalline structure.

[0140] Fig. 6A shows long-term stability of wire oxygenators on CP at 20 pA in lx PBS for a period of 110 days, with the upper right comer shows the setup of the experiment. The WE is SIROF and the CE is Pt.

[0141] Fig. 6B show SEM images of SIROF working electrode at Day 0 and Day 60, with the scale bar at the lower right comer represent 2 pm.

[0142] Fig. 6C shows the measured 02 concentration level after 60 days of operation (13.0 ± 1.5 mg / L), with the picture in the upper right corner shows the setup for the measurement. Results are shown as mean ± SD (n = 3).

[0143] Fig. 6D shows the comparison of LSV (n=3) for the SIROF wires at Day 0 and Day 60 (n = 3) and the corresponding onset overpotential of each sample.

[0144] As disclosed in this embodiment, a miniaturized three-dimensional wire-based oxygen-generating device in mm-scale or sub mm-scale is necessary to support large numbers of cells due to the poor diffusivity of oxygen in aqueous media. The wired oxygenation assembly includes catalyst-coated wires as working electrodes and wires serving as counter electrodes. Wire-based oxygenators have a streamlined manufacturing process that can be readily tuned for material modifications. The large interfacial area of a wire provides a greater area for catalyst loading and better oxygen distribution than 2D systems. Electrochemical testing has shown that wire-based assemblies operate at lower potentials than previously fabricated thin film devices, which provide the advantages of lower power consumption and avoiding competing side reactions.

[0145] In some embodiments, wires coated with catalytic materials, such as iridium oxide 3D fuzzy graphene. The coating of selective overlayers including transition metal oxides does not require any patterning of deposited material, making the manufacturing process significantly faster and less complex. It allows the easy fabrication and control over the nanomorphology of the electrocatalyst by using straightforward synthesis approaches including electrochemical, hydrothermal, as well as sol-gel synthesis. The ability to maintain stability and compliance at temperatures higher than conventional polymeric flexible substrates allows the implementation of annealing and hydrothermal processes to enhance catalyst performance. Additionally, the flexibility of a wire allows it to assume a variety of form factors, which can be readily customized to oxygenate regions of varying shapes and sizes. Various working-counter electrode configurations are explored including wire-wire, wire-coil, coil-wire, and coil-coil geometry to ensure longevity and maximum device performance.Embodiment 2

[0146] Fig. 7 shows another embodiment of the ecO device with localized oxygenation. In particular, the ecCh device is a miniaturized device includes an on-site oxygenator and a house of engineered cells providing customized living therapeutics.

[0147] In one embodiment, the ecCh device includes one or more miniaturized electronics, a miniaturized power unit, and a miniaturized wireless communication unit. In one embodiment, the house of the engineered cells includes a mesh in a cylindrical shape, and working and counter electrodes of the on-site oxygenator are arranged inside the house, while other parts of the on-site oxygenator, e.g. electronics, power unit, communication unit, are encapsulated and disposed next to the house.

[0148] In one embodiment, one or more of the electronics, power unit, and wireless communication unit are mm-scale.

[0149] In one embodiment, one or more of the electronics, power unit, and wireless communication unit are sub-mm-scale.

[0150] In one embodiment, the ecCh device includes immunoisolating biomaterials and / or membranes. In one embodiment, the ecCh device is implanted into a subject using facile, minimally invasive method, e.g., delivered by trocar.

[0151] Table 1 shows the ecCh product profile of the present invention.

[0152] In one embodiment, the ecO2 device uses miniaturized printed circuit board (PCB). In an alternative embodiment, the present invention reduces size of the device and extends lifetime of the device with miniaturized electronics by integrating the electronics in CMOS. In particular, as shown in Fig. 8, the left panel shows an ecO2 hardware design using cm-scale electronics consuming higher idle power. The right panel shows an improved ecO2 hardwaredesign, in which the ecCh electronics / parts are integrated with a 28 nm CMOS system on mm- scale chip. 1x1 mm bare die silicon wire bonded to pads.[001531 In one embodiment, the present invention has ~0.6 mm x -0.4 mm bare die version of the ecO2 electronics design, and thus reduces power consumption to about <3pW, which is one order of magnitude improvement. Miniaturized electronics reduces unit cost by reducing power, size, and burden, by an order of magnitude, as well as enabling minimally-invasive implantation. In one embodiment, the present invention tapeout a -0.6 mm x -0.4 mm version of the ecO2 design, and thus reducing power consumption to about <3pW.

[0154] Fig. 9 shows an ecO2 Block Diagram for ASIC. In one embodiment, the present invention adopts autonomous control of oxygenation using a real time current measurement and linear regulator, for fully analog circuit design to save power. In one embodiment, the simplified pure analog circuit design of ecCh leverages advanced CMOS fabrication nodes.

[0155] Extreme low power of electronics and oxygenation of the present invention enable smaller multi-year implant lifetime. In one embodiment, the present invention has an estimated power requirement of 2.75pW. A non-rechargeable silver oxide batteries, e.g. commercially available off-shelf batteries, would provide a lifetime of about 17 month. (2x 12mAh Silver oxide batteries) In one embodiment, additional batteries can be stacked while maintaining injectability. In one embodiment, lifetime can be increased to about 34 months for longer implant. Minimized design of the present invention is first of its kind for injectable devices.

[0156] Fig. 10 shows a lateral expanded diagram of a battery empowered ecO2 assembly device according to one embodiment of the invention. In particular, the device 100 includes a flexible PCB or a rigid + flexible PCB 101, one or more batteries 103, ASIC 105, one or more counter electrodes 107, and a working electrode 109.

[0157] In one embodiment, as shown in Fig. 10, the electronic components are placed on top of a substrate having multiple bases which are interconnected in one row. In one embodiment, each of the batteries 103 and the ASIC 105 is placed on an individual base. In one embodiment, a base locating on an end of the row of the multiple bases is connected to one or more counter electrodes, as well as a working electrode.

[0158] In one embodiment, the multiple bases of the substrate are arranged in one row. In one embodiment, the multiple bases of the substrate are arranged in one square. In one embodiment, the multiple bases of the substrate are arranged in a pattern permitting the multiplesbased to be folded in a way permitting the batteries effectively powering the ecO2 device and permitting the ecO2 device working effectively.

[0159] In one embodiment, there is only one counter electrode connected to the base locating at the end of the multiple bases. In one embodiment, there are two counter electrodes connected to the base locating at the end of the multiple bases. In one embodiment, there are three to five counter electrodes connected to the base locating at the end of the multiple bases.

[0160] In one embodiment, there are two batteries 103 assembled into the device 100. In one embodiment, there are one to five batteries 103 assembled into the device 100.

[0161] Fig. 11 shows an innovative assembly process / design for the battery empowered ecO2 device. In particular, the novel assembly process is proposed that makes use of existing and high volume facilities (i.e. flex / rigid PCB processes) to simplify packaging and cost.

[0162] In one embodiment, as shown in Fig. 11, the substrate with electronic components disposed on multiple bases are folded in a way allowing the batteries effectively powering the ecO2, and the ecO2 device working properly. In one embodiment, the base with batteries is folded right next to the base with the ASIC. In one embodiment, the base to which the counter electrode and working electrode attached is arranged to the outer most of all multiple based.

[0163] In one embodiment, as shown in Fig. 11, after the substrate with electronic components disposed on multiple bases are folded, the substrate and the electronic components including batteries 103 and ASIC 105 are encapsulated in an encapsulation shell. In one embodiment, the working electrode and the counter electrode(s) extend out of the encapsulation shell such that it can extend into the cell house / chamber 110 containing engineered cells producing the therapeutics. In one embodiment, the base to which the working electrode and the counter electrode(s) attached forms a part of the encapsulation shell.

[0164] Once the folded substrate and the electronic components are encapsulated, the working electrode and the counter electrode(s) are disposed in the cell house / chamber 110 for providing oxygen to the engineered cells grown therein.

[0165] The foregoing description of the exemplary embodiments of the invention has been presented only for the purposes of illustration and description and is not intended to be exhaustive or to limit the invention to the precise forms disclosed. Many modifications and variations are possible in light of the above teaching.

[0166] While there has been shown several and alternate embodiments of the present invention, it is to be understood that certain changes can be made as would be known to one skilled in the art without departing from the underlying scope of the invention as is discussed and set forth above and below including claims and drawings. Furthermore, the embodiments described above and claims set forth below are only intended to illustrate the principles of the present invention and are not intended to limit the scope of the invention to the disclosed elements.

[0167] Some references, which may include patents, patent applications and various publications, are cited and discussed in the description of this invention is incorporated herein by reference in its entireties for background information only. The citation and / or discussion of such references is provided merely to clarify the description of the present invention and is not an admission that any such reference is “prior art” to the invention described herein. All references cited and discussed in the description of this invention are incorporated herein by reference in their entireties and to the same extent as if each reference was individually incorporated by reference.

Claims

CLAIMSWhat is claimed is:

1. An oxygenation system producing oxygen for therapeutic cells housed in an implanted or external system, the oxygenation system comprising: a mm-scale oxygenator having at least one metal electrode; a miniaturized application-specific integrated circuit (ASIC) controlling an oxygen production by the oxygenator; a miniaturized communication unit; and a miniaturized power unit.

2. The oxygenation system according to claim 1, wherein the miniaturized ASIC is in sub-mm scale.

3. The oxygenation system according to claim 1, wherein the miniaturized communication unit is in sub-mm scale.

4. The oxygenator system according to claim 3, wherein the miniaturized communication unit is a low-power wireless communication unit.

5. The oxygenation system according to claim 1, wherein the miniaturized power unit comprises at least one battery having a diameter of 5 mm or less.

6. The oxygenation system according to claim 1, wherein the oxygenation system has a system diameter of 6 mm or less.

7. The oxygenation system according to claim 1, wherein the oxygenation system is configured to be administered to a subject using a minimum invasive method.

8. The oxygenation system according to claim 7, wherein the minimum invasive method comprises one of syringe injection and trocar delivery.

9. The oxygenation system according to claim 1, wherein the at least one metal electrode comprises a first electrode and a second electrode.

10. The oxygenation system according to claim 9, wherein one of the first and second electrodes comprises at least one catalyst for electrocatalytic oxygen evolution reaction (OER).

11. The oxygenation system according to claim 1, wherein the oxygenation system comprises a foldable substrate to which the mm-scale oxygenator, the miniaturized ASIC, and the miniaturized power unit are attached.

12. An implanted or external system housing therapeutic cells and integrated with an oxygenation system producing oxygen for the therapeutic cells, the implanted or external systems comprising: a cell containment subsystem having a house containing therapeutic cells and nutrition solution comprising water; and an oxygenation system, wherein the oxygenation system comprises a mm-scale autonomous oxygenator; and the oxygenator comprises at least one metal electrode located inside of the house.

13. The implanted or external systems integrated with the oxygenation system according to claim 12, wherein the oxygenation system further comprises a sub-mm application-specific integrated circuit (ASIC) controlling oxygen production.

14. The implanted or external systems integrated with the oxygenation system according to claim 13, wherein the oxygenation system further comprises a sub-mm communication unit.

15. The implanted or external systems integrated with the oxygenation system according to claim 14, wherein the sub-mm communication unit is a low-power wireless communication unit.

16. The implanted or external systems integrated with the oxygenation system according to claim 13, wherein the oxygenation system further comprises at least one battery.

17. The implanted or external systems integrated with the oxygenation system according to claim 16, wherein the at least one battery has a diameter of 5 mm or less.

18. The implanted or external systems integrated with the oxygenation system according to claim 12, wherein at least one metal electrode comprises a first electrode and a second electrode.

19. The implanted or external systems integrated with the oxygenation system according to claim 18, wherein one of the first and second electrodes comprises at least one catalyst for electrocatalytic oxygen evolution reaction (OER).

20. The implanted or external systems integrated with the oxygenation system according to claim 19, wherein the one of the first and second electrodes for electrocatalytic OER comprises iridium oxides.

21. The implanted or external systems integrated with the oxygenation system according to claim 19, wherein the iridium oxides are converted from iridium metal wires.

22. The implanted or external systems integrated with the oxygenation system according to claim 18, wherein the first electrode is in contact with water exists in the nutrition solution in the house.

23. The implanted or external systems integrated with the oxygenation system according to claim 12, wherein the oxygenation system comprises a foldable substrate to which the mm-scale oxygenator, the ASIC, and the at least one battery are attached.

24. The implanted or external systems integrated with the oxygenation system according to claim 12, wherein the oxygenation system has a system diameter of 6 mm or less.

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