Biohybrid retrievable cell therapy platform and applications thereof

Abstract

A retrievable implantable biohybrid system housing engineered cells for producing therapeutics in a subject comprises a frontend chamber housing engineered cells which are configured to produce at least one therapeutics; a backend chamber housing at least one electronic component; wherein a first end of the backend chamber is hermetically connected to the frontend chamber; and a retrievable attachment having a attachment hole, wherein the retrievable attachment is connected to a second end of the backend chamber.

Description

Attorney Docket No. 616146.100616BIOHYBRID RETRIEVABLE CELL THERAPY PLATFORM AND APPLICATIONS THEREOFSTATEMENT AS TO RIGHTS UNDER FEDERALLY-SPONSORED RESEARCH

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

[0002] This application claims priority to U.S. Provisional Patent Application Serial No. 63 / 788,181 (Atty Doc. No. 318US0), filed on April 14, 2025. The disclosure of the application is incorporated herein by reference.

[0003] This application is also a continuation-in-part of PCT / US2025 / 010450 (Atty Doc. No.303WO2) filed on January 6, 2025, PCT / US2026 / 010115 (Atty Doc. No. 314WO2) filed on January 5, 2026, and PCT / US2025 / 035339 (Atty Doc. No. 313WO2) filed on June 26, 2025. The disclosure of the application is incorporated herein by reference.FIELD OF THE INVENTION

[0004] The present disclosure relates generally to the field of biomedical engineering, and more particularly to a retrievable biohybrid cell therapy platform, and applications of the same.BACKGROUND OF THE INVENTION

[0005] 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.Attorney Docket No. 616146.100616

[0006] Cancer immunotherapy has revolutionized oncology, offering durable responses in advanced malignancies. It includes cell therapies like TILs, dendritic cell vaccines, and engineered immune receptor lymphocytes (e.g., CAR T cells), which have shown success in hematological cancers but not solid tumors. Protein-based therapies, such as immune checkpoint blockade (ICB) and cytokines, have advanced solid tumor treatment but often fail to provide lasting responses and can cause severe toxicity. Despite significant investment on these therapy and related therapeutics, current approaches lack an advanced delivery vehicle which provides regulated and continued therapeutics to patients who need long-term medication delivery.

[0007] To address these drawbacks, the inventor has previously designed an implantable biohybrid platform to provide regulated and continuous therapeutics for patients requiring longterm medication delivery. This biohybrid device encapsulates engineered cells that produce the desired therapeutics, with oxygenators supplying oxygen to these cells.

[0008] However, the current design of the biohybrid platform is limited to implantation and cannot be retrieved for purposes such as component replacement, engineered cell replacement, or simply, therapy termination.

[0009] Therefore, a heretofore unaddressed need exists in the art to address the aforementioned deficiencies and inadequacies.SUMMARY OF THE INVENTION

[0010] In light of the foregoing, this invention discloses a retrievable implantable biohybrid system housing engineered cells for producing therapeutics in a subject. The system comprises a frontend chamber housing engineered cells which are configured to produce at least one therapeutics; a backend chamber housing at least one electronic component; wherein a first end of the backend chamber is hermetically connected to the frontend chamber; and a retrievable attachment having an attachment hole, wherein the retrievable attachment is connected to a second end of the backend chamber.

[0011] In one embodiment, the attachment hole is configured to be attached to an internal surface of a cavity inside the subject via an attaching mean.

[0012] In one embodiment, the cavity is the peritoneal cavity.

[0013] In one embodiment, the attaching mean comprises suture.Attorney Docket No. 616146.100616

[0014] In one embodiment, the frontend chamber comprises a support cage having an internal chamber for housing capsules containing the engineered cells.

[0015] In one embodiment, the support cage having a loading port configured to receive the capsules containing the engineered cells.

[0016] In one embodiment, the frontend chamber further comprising a loading cap configured to engage with the loading port.

[0017] In one embodiment, the support case having multiple therapeutic holes which are configured to permit therapeutics produced by the engineered cells passing therethrough.

[0018] In one embodiment, each of the multiple therapeutic holes has a diameter of about 1 mm.

[0019] In one embodiment, the support cage is made of polyetheretherketone (PEEK).

[0020] In one embodiment, an oxygenator is disposed inside the frontend chamber for producing oxygen.

[0021] In one embodiment, the backend chamber comprises a hermetic cannister body and two hermetic cannister ends forming a hermetic chamber.

[0022] In one embodiment, a mechanical assembly support is disposed inside the hermetic chamber.

[0023] In one embodiment, the at least one electronic component is disposed inside the hermetic chamber.

[0024] In one embodiment, one of the two hermetic cannister ends is the first end and comprises at least one chip-hermetic feedthrough connector.

[0025] In one embodiment, the oxygenator and the at least one electrical component are in communication via the at least one chip-hermetic feedthrough connector.

[0026] In one embodiment, the retrievable attachment and the second end of the backend chamber forms an attachments chamber which is configured to house at least one antenna.

[0027] In one embodiment, the retrievable attachment is made of PEEK.

[0028] In one embodiment, the attachment hole having a diameter of about 2 mm and locates in in adjacent to a center of a free end of the retrievable attachment opposite to an end connected to the second end of the backend chamber.

[0029] In one embodiment, the retrievable implantable biohybrid system has a diameter less than about 1.5 mm and a length less than about 6 cm.Attorney Docket No. 616146.100616

[0030] In another aspect of the invention, a treatment procedure for delivering therapeutics to a subject comprises obtaining one or more capsules housing engineered cells and one or more retrievable biohybrid devices; loading the one or more capsules into the one or more retrievable biohybrid device; delivering the one or more retrievable biohybrid device into an internal cavity of a subject; attaching the one or more retrievable biohybrid device to a wall of the internal wall of the subject.

[0031] In one embodiment, the procedure further comprises removing the one or more retrievable biohybrid device from the subject after a treatment period.

[0032] In one embodiment, the treatment period ranges between about 10-90 days.

[0033] In one embodiment, the engineered cells produce one or more therapeutics during the treatment period.

[0034] In one embodiment, the one or more retrievable biohybrid device comprises multiple retrievable biohybrid device; wherein the multiple retrievable biohybrid device are attached to each other.

[0035] In one embodiment, each of the one or more retrievable biohybrid devices comprises a frontend chamber configured to house the one or more capsules, a backend chamber configured to house one or more electronic components.

[0036] In one embodiment, the frontend chamber configured to house the one or more capsules and comprises an oxygenator, a backend chamber configured to house one or more electronic components; wherein the oxygenator is electronically connected to the one or more electronic components.

[0037] In one embodiment, at least one of the frontend chamber and the backend chamber comprises an attachment hole, wherein the one or more retrievable biohybrid device are attached to the wall of the internal cavity of the subject via the attachment hole.

[0038] In one embodiment, the one or more therapeutics treats a medical condition of the subject.

[0039] In one embodiment, the subject is a human or a non-human mammal.

[0040] In one embodiment, the internal cavity is the peritoneal cavity of the subject.

[0041] These and other aspects of the present invention will become apparent from the following description of the preferred embodiment taken in conjunction with the followingAttorney Docket No. 616146.100616drawings, although variations and modifications therein may be affected without departing from the spirit and scope of the novel concepts of the disclosure.BRIEF DESCRIPTION OF THE DRAWINGS

[0042] The accompanying drawings illustrate one or more embodiments of the invention and together 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.

[0043] Fig. 1 illustrates an schematic view of the retrievable implantable biohybrid system / device according to one embodiment of the invention.

[0044] Fig. 2 illustrates an exploded view of the retrievable implantable biohybrid system / device according to the embodiment shown in Fig. 1.

[0045] Fig. 3. illustrates an exploded view of the retrievable implantable biohybrid system / device according to another embodiment of the invention.

[0046] Fig. 4 illustrate lateral views of the retrievable implantable biohybrid system / device according to the embodiment shown in Fig. 3.

[0047] Fig. 5 shows a photograph of an assembled retrievable implantable biohybrid system / device according to one embodiment of the invention.

[0048] Fig. 6A shows a chart validating the current generation capability of the retrievable implantable biohybrid system / device.

[0049] Fig. 6B shows a chart validating the oxygenation capability of the retrievable implantable biohybrid system / device.

[0050] Fig. 7A shows a microscopic photograph of the alginate capsules containing the engineered ipilimumab producing ARPE-19 cells before implantation.

[0051] Fig. 7B shows a microscopic photograph of the alginate capsules containing the engineered ipilimumab producing ARPE-19 cells at D60 after implantation.

[0052] Fig. 8A shows a chart reflecting the production of ipilimumab by the engineered ipilimumab producing ARPE-19 cells between DO - D60 after implantation.

[0053] Fig. 8B shows a chart reflecting the production of hIL12 by the engineered ipilimumab producing ARPE-19 cells between DO - D60 after implantation.

[0054] Fig. 9 shows a chart reflecting the currents generated in the retrievable implantableAttorney Docket No. 616146.100616biohybrid system / device.

[0055] Fig. 10 shows a flow chart of lifecycle / use of the retrievable implantable biohybrid system / device.

[0056] Fig. 11A shows representative LC-MS Spectra for Z2A19 after purification.

[0057] Fig. 1 IB shows representative NMR Spectra for Z2A19.

[0058] Fig. 12A shows chemical structure of Z2A19.

[0059] Fig. 12B shows surface characterization of Z2A19 by XPS.DETAILED DESCRIPTION OF THE INVENTION

[0060] 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.

[0061] 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.

[0062] One of ordinary skill in the art will appreciate that starting materials, biologicalAttorney Docket No. 616146.100616materials, 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.

[0063] 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.

[0064] 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.

[0065] 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.Attorney Docket No. 616146.100616

[0066] 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.

[0067] 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.

[0068] 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 / or components, but do not preclude the presence or addition of one or more other features, regions, integers, steps, operations, elements, components, and / or groups thereof.

[0069] 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.Attorney Docket No. 616146.100616

[0070] 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.

[0071] 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.

[0072] 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.

[0073] 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.

[0074] 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 causingi mmunol ogi cal rej ecti on .

[0075] 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.

[0076] As used in the disclosure, the term “therapy” refers to any protocol, method, and / or agent 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.

[0077] 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 ofAttorney Docket No. 616146.100616microspheres disclosed herein). In certain embodiments, the terms refer to the reduction of pain associated with one or more diseases or conditions.

[0078] 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.

[0079] As used in the disclosure, “retrievable” refers to a property of a device or component which makes the device / component that can be removed or extracted from its operational environment after use. That is, the design and construction of the device allow for its safe and effective recovery without causing significant damage to the device or the surrounding environment. The term encompasses the ability to access, detach, and withdraw the device or component in a manner that maintains its integrity and functionality for potential reuse, refurbishment, or disposal.

[0080] 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 wireless communication. Particularly, the “low-power wireless communication unit” is preferred to beAttorney Docket No. 616146.100616Bluetooth low energy wireless communication unit.

[0081] As used herein, the term “biomedical material” or “biomedical materials” refers to biocompatible structural and / or encapsulation materials suitable for use in or on the implantable biohybrid device, including the support cage, housing, front-end chamber, backend encapsulation, manifolds, and related components that may contact, or be exposed to, a subject’s tissues or bodily fluids. Biomedical materials include, without limitation, medical-grade polymers, resins, silicones, elastomers, and other biomaterials that provide adequate mechanical integrity, chemical stability, and manufacturability (for example, allowing formation of thin-walled structures and pores) while permitting required mass transport of oxygen, nutrients, waste products, and therapeutic agents. Non-limiting examples of biomedical materials include polyether ether ketone (PEEK), medical -grade polyurethane, polyethylene terephthalate, polycarbonate, biomed-clear-type resins, silicone and silicone-based encapsulants, medical-grade silicone elastomers (including liquid silicone rubber), and surface- or bulk-modified variants thereof, as well as other functionally similar biocompatible polymers, resins, elastomers, coatings, and composite materials that can be used in place of, or in addition to, a biomedical resin to form at least a portion of the device.

[0082] As used herein, the term “biomedical resin” refers to a polymeric or resinous material suitable for use in or on an implantable or wearable medical device, including, without limitation, device housings, cages, structural supports, caps, manifolds, and overmolded or encapsulated regions. A biomedical resin is biocompatible, as defined herein, and exhibits mechanical stability, chemical resistance, and manufacturability compatible with forming thin-walled structures, pores, openings, and rounded or “soft” features as described in this disclosure. Non-limiting examples of biomedical resins include poly etheretherketone (PEEK), polyurethane, polyethylene terephthalate (PET), polycarbonate, Biomed-clear-type resins, and other medical-grade thermoplastics and thermosets such as medical-grade polyethylene, polypropylene, polyamides, and copolymers or blends thereof. Biomedical resins may be provided in unmodified (neat) form or may be surface-modified and / or bulk-modified, for example by grafting, coating, or incorporating small molecules, oligomers, or polymers to adjust one or more properties such as protein adsorption, inflammatory cell adhesion, fibrotic tissue ingrowth, wettability, or permeability. Unless otherwise indicated, the term “biomedical resin” encompasses both small-molecule-modified and unmodified materials suitable for forming atAttorney Docket No. 616146.100616least a portion of the frontend chamber, support cage, retrievable attachment, or other structural components of the biohybrid device.

[0083] As used herein, the term “small-molecule-modified biomedical resin” refers to a biomedical resin in which one or more small molecules are associated with the resin in a surface-modified and / or bulk-modified fashion. In certain embodiments, the small molecules provide a medical function. In certain embodiments, the biomedical resin forms at least part of the outer housing or cage that contains the cell-laden capsules and includes pores or openings (for example, around 1 mm rounded pores) configured to retain the capsules while permitting diffusion of oxygen, nutrients, wastes, and secreted therapeutic agents. In some embodiments, the biomedical resin is used for coating part or whole device. In some embodiments, the outer housing material is modified with Z2A19 or similar small-molecule moieties to reduce fibrosis, protein adsorption, and / or inflammatory cell adhesion at the material-tissue interface, as described herein. Small-molecule modification may be achieved, for example, by covalent attachment, grafting, adsorption, interpenetrating networks, or blending of the small molecule(s) with the resin, and may be applied to biomedical resin in whole or in part, including only selected surfaces or regions of the housing. Unless otherwise indicated, the term“small-molecule-modified biomedical resin” encompasses biomedical resin bearing any antifibrotic, antifouling, or bioactive small molecules, including, but not limited to, Z2A19 and related alginate-derived or synthetic analogs(e.g. other Zy Ax molecules), configured to enhance biocompatibility and long-term function of the implantable biohybrid device.

[0084] In certain embodiments, the entire device, or any portion thereof, is housed in one or more biomedical materials as defined herein. For example, the cage, housing, front-end chamber, backend chamber, manifolds, connectors, and any external or tissue-facing surfaces of the device may be formed entirely from, or encapsulated by, biomedical materials selected to provide adequate mechanical strength, flexibility, chemical stability, and biocompatibility while permitting required mass transport of oxygen, nutrients, waste products, and therapeutic agents. Such biomedical materials may include medical-grade polymers, resins, silicones, elastomers, coatings, and composite structures, in unmodified or surface- or bulk-modified forms, and may be used individually or in combination to provide a continuous or segmented housing that isolates internal device components from the surrounding tissue environment while maintaining desired functional performance.Attorney Docket No. 616146.100616

[0085] As used in the disclosure, “PEEK” refers to Polyether Ether Ketone, which is a high-performance engineering thermoplastic characterized by its excellent mechanical properties, chemical resistance, and high thermal stability. PEEK is often used in medical devices, aerospace, automotive, and other demanding applications due to its durability and biocompatibility.

[0086] 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.

[0087] The present invention delineates a retrievable implantable biohybrid platform designed to deliver therapeutics for patients necessitating long-term medication administration in a regulated and continuous fashion. This implantable biohybrid device encapsulates engineered cells capable of producing the desired therapeutics, with integrated oxygenators supplying essential oxygen to these cells. The engineered cells are programmed to produce and release therapeutics in response to specific signals, such as electrical or optical pulses. Upon implantation at an appropriate site within the patient, such as subcutaneously, the device operates autonomously to fulfill its therapeutic functions. Additionally, the implantable biohybrid platform incorporates a retrievable structure, facilitating its removal post-implantation for purposes such as component or engineered cells replacement.Example 1 Device Design

[0088] As shown in Figs. 1-2, a retrievable implantable biohybrid system 10 includes a frontend chamber 11, a backend chamber 13, and a retrievable attachment 15.

[0089] In certain embodiments, the frontend chamber 11 is engineered to house one or more engineered cell capsules, oxygenators providing oxygen to the engineered cells in the cell capsules, a support cage 113, and a cell capsule loading port equipped with a cap 111.

[0090] In certain embodiments, the backend chamber 13 includes a hermetically sealed titanium canister that encloses the electronic components essential for the control and operation of the biohybrid device, such as the printed circuit board (PCB) and controller.Attorney Docket No. 616146.100616

[0091] In certain embodiments, the retrievable attachment 15 features a suture hole / attachment hole and a compartment designed to house one or more antennas to facilitate the communication functions of the biohybrid device.

[0092] In certain embodiments, the frontend chamber 11 and the retrievable attachment 15 are affixed to either end of the backend chamber 13.

[0093] As shown in Figs. 3-4, a retrievable implantable biohybrid system includes a frontend chamber 21, a backend chamber 23, and a retrievable attachment 25.

[0094] In certain embodiments, the frontend chamber 21 is engineered to house one or more engineered cell capsules, oxygenators 215 providing oxygen to the engineered cells in the cell capsules, a support cage 213, and a cell capsule loading port equipped with a cap 211. In certain embodiments, the frontend chamber 21 has a frontend suture hole / attachment hole 219 such that the device can be attached to the internal cavity of a patient via suture or other attachment means via the frontend suture hole / attachment hole 219.

[0095] In certain embodiments, the backend chamber 23 includes a hermetically sealed titanium canister 231 that encloses the electronic components 235 / 239 essential for the control and operation of the biohybrid device, such as the printed circuit board (PCB) 235 and controller.

[0096] In certain embodiments, the retrievable attachment 25 features a backend suture hole / attachment hole 251 and a compartment designed to house one or more antennas to facilitate the communication functions of the biohybrid device. In certain embodiments, one of the frontend suture hole / attachment hole 219 and the backend suture hole / attachment hole 251 is used for attaching the device to the internal cavity of the patient via a suture or other attachment means, e.g. glue, staples, etc. In certain embodiments, both of the frontend suture hole / attachment hole 219 and the backend suture hole / attachment hole 251 are used for attaching the device to the internal cavity of the patient via sutures or other attachment means.

[0097] In certain embodiments, the frontend chamber 21 and the retrievable attachment 25 are affixed to either end of the backend chamber 23.

[0098] In certain embodiments, the retrievable implantable biohybrid system 10 has a diameter about 1.4 cm. In certain embodiments, the retrievable implantable biohybrid system 10 has a diameter between about 1.3. -1.5 cm. In certain embodiments, the retrievable implantable biohybrid system 10 has a diameter between about 1.2. -1.6 cm. In certain embodiments, the retrievable implantable biohybrid system 10 has a diameter between about 1.0 -1.4 cm. In certainAttorney Docket No. 616146.100616embodiments, the retrievable implantable biohybrid system 10 has a diameter between about 1.4-1.8 cm. In certain embodiments, the retrievable implantable biohybrid system 10 has a diameter between about 1.0 - 2.0 cm. In certain embodiments, the retrievable implantable biohybrid system 10 has a diameter between about 0.5-5.0 cm.

[0099] In certain embodiments, the retrievable implantable biohybrid system 10 has a length between about 5.5 - 5.8 cm. In certain embodiments, the retrievable implantable biohybrid system 10 has a length between about 5.3 - 6.0 cm. In certain embodiments, the retrievable implantable biohybrid system 10 has a length between about 5.1 - 6.2 cm. In certain embodiments, the retrievable implantable biohybrid system 10 has a length between about 4.9 -6.6 cm. In certain embodiments, the retrievable implantable biohybrid system 10 has a length between about 4.7 - 6.8 cm. In certain embodiments, the retrievable implantable biohybrid system 10 has a length between about 4.5 - 7.0 cm. In certain embodiments, the retrievable implantable biohybrid system 10 has a length between about 2.0 - 10.0 cm.

[0100] In certain embodiments, the retrievable implantable biohybrid system 10 has a length between about 4.5 - 5.0 cm. In certain embodiments, the retrievable implantable biohybrid system 10 has a length between about 5.0 - 5.5 cm. In certain embodiments, the retrievable implantable biohybrid system 10 has a length between about 5.8 - 6.2 cm. In certain embodiments, the retrievable implantable biohybrid system 10 has a length between about 7.2 -7.0 cm.

[0101] In certain embodiments, one or both of the frontend suture hole / attachment hole 219 and the backend suture hole / attachment hole 251 have a diameter between about 1.5-3 mm. In certain embodiments, one or both of the frontend suture hole / attachment hole 219 and the backend suture hole / attachment hole 251 have a diameter between about 1.4-3.1 mm. In certain embodiments, one or both of the frontend suture hole / attachment hole 219 and the backend suture hole / attachment hole 251 have a diameter between about 1.3-3.2 mm. In certain embodiments, one or both of the frontend suture hole / attachment hole 219 and the backend suture hole / attachment hole 251 have a diameter between about 1.2-3.3 mm. In certain embodiments, one or both of the frontend suture hole / attachment hole 219 and the backend suture hole / attachment hole 251 have a diameter between about 1.1 -3.4 mm. In certain embodiments, one or both of the frontend suture hole / attachment hole 219 and the backend suture hole / attachment hole 251 have a diameter between about 1.0-3.5 mm. In certainAttorney Docket No. 616146.100616embodiments, one or both of the frontend suture hole / attachment hole 219 and the backend suture hole / attachment hole 251 have a diameter between about 0.5-4.0 mm. In certain embodiments, one or both of the frontend suture hole / attachment hole 219 and the backend suture hole / attachment hole 251 have a diameter less than about 5.0 mm.

[0102] Fig. 2 provide an exploded view of the retrievable implantable biohybrid system. As shown in Fig. 2, the frontend chamber 11 includes a support cage 113 for housing alginate capsules containing engineered cells deigned to produce therapeutics. In certain embodiments, the support cage 113 is made of biomedical materials. In certain embodiments, the support cage 113 has therapeutics holes permitting the produced therapeutics to pass therethrough so as to enter into the patient’s body. In certain embodiments, the therapeutics holes have a diameter of about 1 mm. In certain embodiments, the therapeutics holes have a diameter between about 0.9 - I.1 mm. In certain embodiments, the therapeutics holes have a diameter between about 0.8 - 1.2 mm. In certain embodiments, the therapeutics holes have a diameter between about 0.6 - 1.4 mm. In certain embodiments, each therapeutic hole may be equipped with a semi-permeable membrane that selectively permits the passage of produced therapeutics.

[0103] In certain embodiments, the front end has a loading port 112 having a diameter allowing the loading and removing the alginate capsules containing engineered cells into and from the support cage 113. In certain embodiment, the loading port 112 has a loading port cap 111 for sealing the loading port 112 when necessary, e.g. when the device is implanted inside a patient’s peritoneal cavity.

[0104] In certain embodiments, the frontend chamber 11 includes an oxygenator 115 which is disposed inside the frontend chamber 11 and provide oxygen to the engineered cells capsuled. In certain embodiments, the oxygenator 115 comprises one or more back-to-back oxygenator chips. In certain embodiments, the oxygenator 115 comprises a wired-form oxygenator.

[0105] In certain embodiments, the frontend chamber 11 further includes an encapsulation of chip-hermetic feedthrough connection base 117, which permits the electrical and / or informational communication between the oxygenator 115 and the electronic components 135, without exposing the physical connection between the two to the liquid in the frontend chamber I I. In certain embodiments, the oxygenator 115 / 215 has a SIROF working electrode 2153, and a Pt coil counter electrode 2151. Other embodiments of the electrodes for the oxygenator areAttorney Docket No. 616146.100616disclosed in PCT Application serial number PCT / US2026 / 010115 fried on January 5, 2026, which is hereby incorporated by references.

[0106] In certain embodiments, the backend chamber 13 includes a hermetic cannister body 131 and two hermetic cannister ends 133 forming a sealed backend chamber 13. The backend chamber 13 further includes electronic components 135 necessary for operation and function of the biohybrid device, such as PCB, controller, storage, and etc, and are disposed inside the sealed backend chamber. In certain embodiments, the assembly support mechanicals 137 are disposed inside the sealed backend chamber 13, reinforce the stricture of the backend chamber 13, and / or provide organized placement of the electronic components.

[0107] In certain embodiments, the two hermetic cannister ends 133 includes electronic pins 1331 which enable the information and / or electronic communication between the oxygenator 115 and the electronic components 135, or between the antennas 153 and the electronic components 135.

[0108] In certain embodiments, the backend chamber 13 is equipped with a battery 139 that serves as the power source for the biohybrid device. This battery may be designed to be either replaceable or rechargeable, with the latter option supporting both wired and wireless recharging methods.

[0109] The retrievable attachment 15 features an attachment hole 151 located at the end opposite to the surface that attaches to the backend chamber 13. In certain embodiments, this attachment hole 151 is centrally positioned at the end part of the retrievable attachment 15. When the retrievable attachment 15 is affixed to the backend chamber 13, an antenna chamber is formed between them to house one or more antennas 153.

[0110] In certain embodiments, the ARPE-19 cells are encapsulated in alginate spheres which are injected into the biohybrid device through the loading port 112, and the cap 111 is mechanically placed, entrapping the alginate spheres in the frontend chamber 11.

[0111] In certain embodiments, the biohybrid device loaded with the engineered cells is inserted through an opening of about 15 mm into the peritoneal space of an animal or human. In certain embodiments, the opening is between about 10-20 mm.

[0112] In certain embodiments, the end of the biohybrid device features a mechanically locking cap.Attorney Docket No. 616146.100616

[0113] In certain embodiments, the biohybrid device is attached to a surface of the patient’s peritoneal cavity via a fastening means attached to the retrieving hole 151. In certain embodiments, the biohybrid device is loosely sutured using the retrieving hole 151 at the end opposite the loading port 112. In certain embodiments, this suture is intentionally designed to be loosely secured to the wall of the peritoneal cavity, allowing the device to hang freely and maintain rotational mobility.

[0114] In certain embodiments, the biohybrid device can be retrieved after use. In certain embodiments, the biohybrid device can be retrieved after use by first locating it within the peritoneal cavity, where it is loosely sutured to the wall. The suture serves as a guide to localize the device for retrieval. Once located, the device can be removed via the suture. In certain embodiments, the device can be removed through the same port that was used for its insertion.

[0115] As discussed above, the present invention distinguishes itself from the prior art in following aspect:

[0116] The primary objective of the biohybrid device is to sustain high-density allogeneic cells in a retrievable form factor for a period of 9-12 weeks within the intraperitoneal space. This device is engineered to produce therapeutic agents from encapsulated ARPE-19 cells that have been genetically modified to produce cytokines, e.g. Interleukin- 12 (1L12), monoclonal antibodies, e.g., Ipilimumab (Ipi), or other desired therapeutics. The encapsulated cells are maintained in a viable state, ensuring continuous production of the therapeutic agents over the specified duration.

[0117] In certain embodiments, the biohybrid device's frontend chamber integrates a support cage equipped advanced oxygenator chip for housing cell capsules. This oxygenator is capable of operating in either constant current or constant voltage mode, offering operational flexibility. To facilitate this, a current (I) or voltage (V) is applied to the oxygenator's contact pads, relative to an on-chip counter electrode.

[0118] The primary function of the oxygenator chip is to ensure the survival and functionality of the encapsulated cells by providing the necessary oxygenation. The chip can be configured to run in constant current mode, where a steady current is maintained, or in constant voltage mode, where a steady voltage is applied. This flexibility allows for precise control over the oxygenation process, which is critical for maintaining the viability of the encapsulated cells.Attorney Docket No. 616146.100616

[0119] The oxygenator chip is connected to a PCB and battery, which are enclosed in a hermetic can or cylinder. This connection is made through hermetic feedthroughs to ensure the integrity and protection of the electronic components. The electronic hardware inside the can includes commercial electronic components such as a microcontroller and a communications chip. These components serve as a miniature potentiostat, controlling the application and measurement of current (I) and voltage (V).

[0120] Current measurements and battery power data can be stored on board for later retrieval or transmitted when communication is enabled or desired. A monopole antenna on the back end is used for communications, such as Bluetooth Low Energy (BLE). This antenna is housed outside the hermetic metallic can and connected through a hermetic passthrough. The antenna can also be internal if the can is made of ceramic or polymer.

[0121] External communication and control can be enabled to assess device function during or after assembly, during animal testing, or after animal / human use to review the operational history or test device function. This bi-directional communication can be facilitated through an application.

[0122] Before implementation in humans, the device is switched to an autonomous mode, where the control of the voltage is adjusted in response to measurements of oxygenator current, up to a set safety threshold determined by known limits for byproduct production, based on voltage above the oxygen production onset. This ensures the device operates safely and effectively within the established parameters.

[0123] In certain embodiments, the engineered cells are ARPE-19 cells producing biologies such as IL 12 and Ipi. In certain embodiments, the biohybrid device houses a total of about 60 million cells, with options for smaller devices for single therapy or higher cell densities. In certain embodiments, engineered cells are designed to produce other therapeutics proven to be effective in treatment.

[0124] In certain embodiments, the cell capsules are alginate capsules having a diameter of about 1.5 mm, which have proven effective in vivo for up to a year. The capsules are larger than the cage structure's pore size (about 1 mm) to ensure secure housing.

[0125] In certain embodiments, the support cage of the frontend chamber features about 1 mm rounded pores to prevent fibrotic bridging and minimize stress on the tissue and capsules, small-molecule-modified biomedical resin is the preferred material, but other biocompatibleAttorney Docket No. 616146.100616materials like polyurethane, polyethylene terephthalate, polycarbonate, medical-grade liquid silicone rubber elastomer, and PEEK are also viable options. In certain embodiments, the support cage has rounded or “soft” edges targeted to avoid damaging tissue or capsules, so as to minimize stresses that can trigger foreign body response.

[0126] In certain embodiments, the biohybrid device has a cylindrical shape, which maximizes the diffusible surface area for enhanced mass transport. It is designed to fit easily into a 15 mm trocar or port, with an outer diameter of less than 15 mm and a length of up to 6 cm. The edges are rounded to facilitate insertion.

[0127] In certain embodiments, a single suture hole / attachment hole (retrievable hole 151) having a diameter of about 2 mm is centered at one end of the biohybrid device to affix it to the peritoneal cavity wall, ensuring localization for retrieval and consistent communication. The suture hole / attachment hole is designed to avoid trapping organs or tissues.

[0128] In certain embodiments, the back-end electronics are encapsulated and protected by a hermetic can, and the front-end connections are encapsulated with silicone adhesives or thin film encapsulations like parylene C or oxides.

[0129] In certain embodiments, the oxygenator is a thin film device with dimensions of approximately 9 mm in width and 13.5 mm active as portion, designed for double-sided oxygenation. In certain embodiments, the size of the customizable according to the chamber size and cell density.

[0130] In certain embodiments, the biohybrid device uses commercially available medicalgrade primary cells, such as the Resonetics P200, with sufficient capacity to fit within the can size.

[0131] In certain embodiments, Bluetooth unit is used for development, with the capability to read out currents, set currents, and show battery levels. The device can operate autonomously, adjusting voltage based on current readings up to a safety threshold.

[0132] In certain embodiments, the alginate capsules and IL12 production help prevent fibrosis, ensuring the cells remain viable even if slightly fibrosed.Example 2 Device Preparation, Loading, Implantation, and RetrievalAttorney Docket No. 616146.100616

[0133] In certain embodiments, the present disclosure provides methods for preparing, loading, implanting, and retrieving a retrievable implantable biohybrid system 10 configured as a cell-based factory for intraperitoneal use.

[0134] As shown in Figs. 3-4, the biohybrid system 20 may include a frontend chamber 21, a backend chamber 13, and a retrievable attachment 25. In some embodiments, the frontend chamber 21 includes a support cage 213, a loading port 212 with a loading port cap 211, and an oxygenator 215, having a S1ROF working electrode 2153, and a Pt coil counter electrode 2151, configured to generate oxygen within the chamber. The frontend chamber also includes a frontend suture hole / attachment hole 219 for attaching the device / system to a internal cavity of the patient.

[0135] The backend chamber 23 may include a hermetically sealed cannister body 231 and hermetic cannister ends 233 enclosing electronic components 235 and a power source, such as a battery 239. The retrievable attachment 25 may include an attachment hole 251 configured to receive a suture for securing the device and facilitating retrieval.

[0136] In certain embodiments, the biohybrid device is supplied as a fully assembled and sterilized platform comprising the frontend chamber 21, the backend chamber 23, and the retrievable attachment 25. The assembled device may be sterilized and packaged in a sterile configuration suitable for clinical handling. In some embodiments, encapsulated engineered cells are prepared separately and provided in a sterile syringe or vial. For example, engineered ARPE-19 cells may be encapsulated in alginate capsules and configured to produce one or more therapeutic agents, such as interleukin- 12 (IL-12), ipilimumab, or combinations thereof.

[0137] The engineered cells for produced therapeutics and other agents in a patient’s body after the implantation of the device / system are disclosed in PCT application serial number PCT / US2025 / 035339 filed on June 26, 2025, which is here by incorporated by references.Total Cell Number and Capsule Loading Parameters

[0138] In certain embodiments, the total number of cells per implantable device is determined by the combination of capsule packing volume, capsule density, and cell density within each capsule. The encapsulated cell formulations may be prepared at cell densities in the range of about 5. Ox 10A7 cells / mL to about 1.5xl0A8 cells / mL (50 million to 150 million cellsAttorney Docket No. 616146.100616per mL), such as for dual -therapy combinations including interleukin- 12 (TL-12) and ipilimumab. In some embodiments, each device is loaded with approximately 2 mL of packed capsules. The capsules may be present in the packed volume at a density of about 300 to about 450 capsules per mL of packed capsule suspension. At a single-layer capsule cell density of about 1.0*10A8 cells / mL, this corresponds to an average of about 100,000 cells per capsule, for example about 100,000 ± 15,000 cells per single-layer capsule. At a core-shell capsule cell density of about 5.0*10A7 cells / mL, this corresponds to an average of about 25,000 cells per capsule, for example about 25,000 ± 5,000 cells per core-shell capsule. In some higher-density single-layer embodiments, the single-layer capsules are loaded to provide an average of about 150,000 cells per capsule, for example about 150,000 ± 20,000 cells per capsule. These parameters may be selected to provide sufficient total cell numbers and per-capsule productivity to support sustained in vivo production of the target biologies, such as antibody or cytokine therapeutics, following implantation of the device.

[0139] In illustrative embodiments, the overall distribution of capsule types in a given device can include both core-shell capsules and single-layer capsules, where the core-shell fraction may represent a lower-density population (for example, approximately 50% of the single-layer cell density). For devices loaded with approximately 2 mL of packed capsules at the above-described capsule and cell densities, the resulting total viable cell count per device can fall within a range of about 1.2*10A7 to about 1.6><10A8 cells (12 million to 160 million cells per device), depending on the proportion of single-layer versus core-shell capsules and the specific cell density selected for each capsule type. This per-device cell number range is chosen in view of manufacturing feasibility (e.g., achievable production batch sizes and capsule yields), cell viability at high packing densities, and the anticipated in vivo productivity needed to deliver therapeutically effective levels of the expressed biologies. In particular, higher total cell counts are advantageous for production of systemic biologies such as antibodies, where sustained, high-level secretion into the host circulation is desired, and the specified ranges provide a balance between sufficient therapeutic output and practical constraints on capsule fabrication, device loading, and implantation.Capsule Size and MaterialsAttorney Docket No. 616146.100616

[0140] In certain embodiments, the therapeutic cells are encapsulated within substantially spherical alginate capsules having a nominal diameter of about 1.5 mm. The capsules are formed as single-component, single-material capsules (for example, calcium-crosslinked alginate) using manufacturing processes that have been demonstrated to be robust, reproducible, and scalable. The 1.5 mm capsule size is selected relative to the device cage or housing such that the capsules are larger than the characteristic pore size of the surrounding cage structure, thereby preventing the capsules from passing or leaking through the cage pores while still allowing free diffusion of soluble factors. Alginate is selected as the capsule material in view of its extensive prior use in vivo, established biocompatibility, and proven performance in maintaining capsule integrity and function in animal models for periods of at least about one year. In certain embodiments, the use of a single alginate material and single-component capsule structure simplifies manufacturing, quality control, and regulatory characterization, while still providing adequate mechanical robustness and permeability for oxygen, nutrients, and secreted therapeutic molecules.Total Cell Chamber Volume

[0141] In certain embodiments, the device includes a cell chamber configured to receive and house the alginate capsules at a packed or near-packed state, the total internal volume of the chamber being from about 1.8 mb to about 2.5 mL. In some implementations, the chamber volume is between about 1-3 mL. In some implementations, the chamber volume is aboutl.2 mL, about 1.4 mL, about 1.6 mL, about 1.8 mL, about 2.0 mL, about 2.2 mL, about 2.4 mL, about 2.6 mL, or about 2.8 mL. This volume range is selected to accommodate sufficient numbers of encapsulated cells — based on the capsule size, capsule packing density, and cell density per capsule — to achieve therapeutically effective in vivo production of one or more biologic agents. By constraining the chamber volume within this range, the device can house a high total cell load while maintaining adequate interstitial space and pore access for mass transport of oxygen, nutrients, waste products, and the secreted therapeutic molecules. The specified volume also reflects practical considerations for implantation (e.g., overall device size compatible with minimally invasive surgical ports) and manufacturing (e.g., filling, de-airing, and sealing of a defined capsule volume).Cage / Housing Pore Geometry and MaterialsAttorney Docket No. 616146.100616

[0142] In certain embodiments, the cell chamber is defined at least in part by a cage or housing having a plurality of pores or openings with a characteristic pore size of about 1 mm. The pores may be substantially round or rounded, and the edges of the pores and other structural features of the cage are configured with rounded or “soft” transitions. The pore size is selected to be smaller than the diameter of the alginate capsules (e g. 1.5 mm) so that the capsules are retained within the chamber, while the 1 mm opening is sufficiently large to limit or minimize fibrotic bridging across the pores and to maintain open diffusion pathways for extended implantation periods. It should be understand that other sizes can be customized to accommodate the function of the device. The rounding of pore edges and external features is intended to reduce local mechanical stresses on surrounding tissues and on the capsules themselves, thereby decreasing the likelihood of capsule damage, tissue irritation, and foreign body response that could otherwise lead to excessive fibrosis or pore occlusion.

[0143] In certain embodiments, the cage or housing is formed from a biocompatible material such as a medical-grade polymer. Suitable materials include, for example, Biomedclear-type resins or silicone, which may be used in small-molecule-modified or unmodified forms. Such materials are selected for their biocompatibility, mechanical stability, and compatibility with forming thin-walled structures having 1 mm rounded pores. In some embodiments, surface or bulk modifications of these biomaterials may be employed to further reduce protein adsorption, inflammatory cell adhesion, or fibrotic tissue ingrowth. Collectively, the pore size, pore geometry, and housing material are chosen to balance secure capsule retention, efficient mass transport, and mitigation of fibrotic bridging and foreign body responses during the functional lifetime of the implant.Device Form Factor and Radial Delivery of Biologies

[0144] In certain embodiments, the implantable device is configured with an elongated, generally cylindrical form factor in which a frontend cell chamber or “cell factory” is arranged to deliver secreted biologies radially outward into the surrounding body cavity. The cylindrical configuration provides a substantially uniform circumferential surface area through which diffusible therapeutic agents — such as antibodies, cytokines, or other biologies produced by encapsulated engineered cells — can be transported into adjacent tissues and fluids. Evidence from modeling and / or in vivo studies suggests that a one-sided or planar device geometry canAttorney Docket No. 616146.100616limit mass transport and lead to non-uniform exposure of surrounding tissues. The cylindrical form factor is therefore selected to maximize the diffusible surface area per unit volume of cell payload, enhancing radial mass transport and promoting more homogeneous distribution of the therapeutic agents around the device. In some embodiments, the cylindrical geometry is further coordinated with the internal cage and capsule arrangements described herein so that, when implanted in the peritoneal cavity, the device provides efficient radial diffusion of biologies across the full circumference of the cell chamber.Device Size and Laparoscopic Compatibility

[0145] In certain embodiments, the overall device size is selected to be compatible with minimally invasive implantation through a standard laparoscopic port or trocar while still accommodating the desired cell chamber volume and internal components. The device may be dimensioned to have an outer diameter of less than about 15 mm, and a length of less than or equal to about 6 cm. In some specific embodiments, the device has an outer diameter sized to pass readily through a 15 mm trocar and a length of about 5-6 cm, with rounded or otherwise non-sharp edges at its ends and along its exterior surface. The rounded edges and smooth exterior profile are intended to facilitate atraumatic passage through the port, reduce snagging or abrasion of tissue during manipulation, and minimize localized stress concentrations that could exacerbate a foreign body response. These dimensional and geometric constraints are chosen so that the fully assembled device, including the frontend cell chamber and backend housing, can be introduced, positioned, and retrieved through a 15 mm port while still providing sufficient internal volume to house the encapsulated cells, oxygenation components, electronics, and power source required to achieve therapeutic efficacy over the intended implantation period.Suture hole / attachment holes and Device Fixation

[0146] In certain embodiments, the device includes suture features configured to permit secure yet controlled fixation of the device to a wall of the peritoneal cavity or other internal body surface and to facilitate subsequent localization and retrieval. The device may include two suture hole / attachment holes, each having a diameter in the range of about 1.5 mm to about 3 mm, with one suture hole / attachment hole disposed toward each longitudinal end of the device. These suture hole / attachment holes provide attachment points for sutures or other fixation elements and enable multiple deployment configurations.Attorney Docket No. 616146.100616

[0147] In some embodiments, a single device is implanted and affixed using only one of the suture hole / attachment holes, typically at one end of the device, to allow the device to hang freely from the peritoneal wall with some degree of rotational and translational freedom. This configuration promotes consistent communication between the device and the surrounding intraperitoneal environment while reducing mechanical stress on tissues and on the device itself. In other embodiments, multiple devices may be “daisy-chained” together by passing a suture through the suture hole / attachment hole at the front end of one device and the suture hole / attachment hole at the back end of an adjacent device, thereby serially linking multiple devices. In such chained configurations, only one end of the chain is sutured to the peritoneal wall, so that the interconnected devices remain localized within a defined region yet maintain freedom of motion away from the wall. The size and placement of the suture hole / attachment holes are thus selected to permit reliable fixation, controlled localization for retrieval, and flexibility to support either single-device or chained-device configurations, while minimizing the risk of tissue entrapment or excessive tethering that could impact device function or retrieval.Backend Electronics Encapsulation in Hermetic Titanium Can[00148J In certain embodiments, the backend electronics of the implantable device are enclosed within a hermetically sealed metallic housing to protect the electronics from the bodily environment and from failures or degradation of external encapsulation layers. The backend chamber can comprise a hermetic titanium can 231 configured to house one or more printed circuit boards (PCBs) 235, power sources 239, and associated electronic components. The titanium can is sealed, for example by laser welding to a hermetic end plate 233 that incorporates one or more hermetic electrical feedthroughs 1331. The PCB and battery are mounted within the interior of the titanium can and are electrically connected to the hermetic feedthroughs 1331, which in turn provide electrical connection to components located outside the can, such as the oxygenator electrodes and communication antenna. By fully enclosing the PCB 235 and battery 235 within a hermetic titanium can 231, the device ensures that backend electronics remain protected even in the event of failure of external encapsulation materials or ingress of fluid into non-hermetic regions of the device. This architecture provides a robust barrier against moisture and corrosive species, thereby improving reliability and extending the operational lifetime of the electronics.Attorney Docket No. 616146.100616Oxygenator Working Electrode and Counter Electrode

[0149] In certain embodiments, the oxygenator includes a thin-film electrocatalytic working electrode configured to generate oxygen within the cell chamber when an electrical potential is applied. The oxygenator working electrode can be realized as a sputtered iridium oxide (e.g., sputtered iridium oxide film, SIROF) electrode formed on a substrate and dimensioned to fit within the inner chamber of the device. In some implementations, the working electrode has a width of about 5 mm to about 9 mm and a length of about 10 mm to about 15 mm, and is arranged so that both sides of the thin film are exposed to the electrolyte, thereby providing a “double-sided” active surface for oxygen generation. The size and geometry of the working electrode are determined by the dimensions of the inner oxygenation chamber and by the need to achieve double-sided oxygenation to support the desired diffusion profiles within the capsule-containing volume. SIROF is selected as the electrocatalytic material based on its demonstrated stability and performance in vivo in neural and muscle stimulation and recording applications, including resistance to delamination and maintenance of electrochemical characteristics over extended implantation. In other embodiments, alternative stable electrocatalysts suitable for in vivo operation can be employed. The working electrode is electrically coupled to the backend PCB through a hermetic feedthrough using a conductive material, such as a conductive epoxy, which provides both low-resistance electrical connection and mechanical compliance at the interface between the electrode structure and the hermetic feedthrough.

[0150] In certain embodiments, the oxygenator further comprises a counter electrode configured to complement the working electrode and to provide sufficient electrochemical surface area for stable electrolytic operation. The counter electrode can be formed from a platinum wire having a total length of approximately 20 cm to 30 cm, coiled into a helix and disposed along or “hugging” the inner wall of the cage or inner chamber surrounding the working electrode. The coiled platinum counter electrode is arranged so that its turns follow the curvature and length of the inner wall, thereby maximizing its exposed surface area within the available volume. The functional performance of the counter electrode is determined primarily by its effective surface area; accordingly, the wire gauge, coiling pitch, and coil diameter are selected based on the loading volume of the capsule compartment and the overall device size so as to provide adequate area while maintaining the desired form factor. Platinum is chosen as theAttorney Docket No. 616146.100616counter-electrode material due to its extensive predicate use as a stable electrode in chronic electrical stimulation applications, including its resistance to corrosion and maintenance of electrochemical properties over long-term implantation. In other embodiments, other stable metals or metal morphologies suitable for in vivo counter-electrode use can be utilized. The coiled platinum counter electrode is electrically connected to the appropriate hermetic feedthrough by a joining method such as welding, which provides a robust, low-impedance bond compatible with chronic implantation.

[0151] Other embodiments of the electrodes for the oxygenator are disclosed in PCT Application serial number PCT / US2026 / 010115 filed on January 5, 2026, which is hereby incorporated by references.Battery Selection and Power Capacity

[0152] In certain embodiments, the hermetic titanium can 131 / 231 houses a primary battery 139 / 239 configured to supply power to the oxygenator circuitry and associated electronics for the duration of the intended implant period. The battery may comprise one or more commercially available medical -grade primary cells, such as a Resonetics P200 cell or a functionally equivalent battery, selected to fit within the volumetric constraints of the hermetic can while providing sufficient energy capacity. For representative use cases, a battery capacity on the order of about 200 mAh is sufficient to support the anticipated power draw of the PCB and oxygenator over the planned treatment interval, taking into account duty-cycled operation of the oxygenator and periodic communication. The use of commercially available medical-grade primary cells leverages established safety and reliability predicates, simplifies regulatory pathways, and allows predictable performance based on known discharge characteristics. Power consumption is determined by the design of the electronics board and the operating parameters of the oxygenator, and the selected battery capacity is chosen to maintain adequate voltage margins throughout the expected life of the device.Encapsulation of Front-End Electrical Connections

[0153] In certain embodiments, electrical connections between the frontend oxygenated cell chamber and the backend hermetic can are encapsulated with one or more biocompatible materials to enhance connection integrity and device longevity. The regions in which conductors from the oxygenator electrodes interface with the hermetic feedthrough pins can be overmoldedAttorney Docket No. 616146.100616or coated with silicone-based adhesives, such as medical-grade silicone, which provide mechanical strain relief and environmental sealing. In certain embodiments, the frontend and backend chambers are overmolded or coated with the silicone-based biomaterials. In some implementations, these silicone encapsulants are used alone; in other implementations, they are combined with one or more thin-film encapsulation layers to form a multilayer barrier. Suitable thin-film encapsulation materials include parylene C and various oxide coatings, which can be deposited in single or multiple layers to improve resistance to moisture ingress, ionic contamination, and mechanical wear. By encapsulating the front-end electrical connections in this manner, the device improves the long-term stability of the electrical interfaces, reduces the risk of corrosion or shorting in the fluid environment of the cell chamber, and contributes to the overall longevity of both the connections and the device as a whole.Communication Subsystem and Near-Field Operation

[0154] In certain embodiments, the device includes an integrated communication subsystem configured to enable secure, short-range wireless interaction with the backend electronics and / or retrievable attachment 15 / 25. The communication electronics can utilize commercially available off-the-shelf (COTS) communication integrated circuits, supporting protocols such as Bluetooth Low Energy (BLE) and / or near field communication (NFC). The communication performance is governed by the design of the associated circuit and antenna and is intentionally configured to operate in a very near field regime, such that reliable communication occurs only when an external reader or programmer is placed in close proximity (for example, within millimeters) to the implanted or explanted device. This very near field communication configuration enhances security and reduces the likelihood of unintended or unauthorized access to device functions. In certain embodiments, the communication subsystem enables the reading of oxygenator currents, setting or adjustment of currents and other parameters during development or testing, and the ability to shut off or disable the device. Communication can also be used to provide readouts of battery level or other telemetry stored on the PCB. In clinical use, communication may be restricted so that no wireless communication is possible during implantation or normal operation within the body, with communication being enabled only in controlled settings such as pre-implant programming, post-retrieval interrogation, or development environments.Antifibrotic Features and MaterialsAttorney Docket No. 616146.100616

[0155] In certain embodiments, the device incorporates antifibrotic design features and materials to mitigate fibrotic encapsulation and maintain effective mass transport to and from the encapsulated cells. The alginate capsules used to house the therapeutic cells can comprise an alginate formulation such as Z2A19-VLVG, which may be selected for its biocompatibility and reduced fibrotic response profile. The outer housing or cage that contains the capsules can be formed from a biocompatible material such as a Biomedclear-type resin or silicone, and in some embodiments the outer housing material is modified with Z2A19 or similar moi eties to further reduce fibrosis and protein adsorption. In other embodiments, the outer housing may be unmodified. Even where some degree of fibrotic encapsulation occurs, the device is configured so that oxygenation delivered by the oxygenator can maintain cell viability and function, such that the encapsulated cells remain viable and productive despite partial or modest fibrotic coverage. By combining antifibrotic capsule chemistries, optionally modified outer housing materials, and active oxygenation, the device is able to sustain therapeutic cell function in vivo over extended periods, even in the presence of host fibrotic responses.Example 3 - Benchtop Validation of Current / Oxygenation of the Device with Coil CE [00156J Figure 6A illustrates exemplary benchtop validation data demonstrating the current generation capability of the oxygenator subsystem of the implantable biohybrid device when configured with a coil counter electrode (CE). In certain embodiments, the oxygenator comprises a thin-film SIROF working electrode in combination with a platinum coil counter electrode disposed inside the frontend chamber, e.g. along the inner wall of the frontend chamber. As shown in Figure 6A, four separate, fully assembled devices incorporating the coil CE were operated under conditions representative of current production use, namely at an applied potential of about 1.8 V with an approximately 80% duty cycle. Each of the four devices was run continuously for at least three days. Throughout these multi-day tests, none of the devices exhibited electrical shorts, and the measured currents remained stable over time, indicating robust electrochemical performance of the oxygenator circuitry and electrode configuration. The current traces plotted in Figure 6A demonstrate that the coil CE configuration yields repeatable and predictable current profiles across devices and cycles, with improved reliability and manufacturing yield relative to devices using an on-chip counter electrode. These data support that the coil CE architecture provides a stable and reproducible current source suitable for long-term duty-cycled oxygen generation within the implantable device.Attorney Docket No. 616146.100616

[0157] Figure 6B presents benchtop validation data of the oxygenation performance of the same devices configured with a coil counter electrode and a working electrode. For these measurements, the electrolyte surrounding the oxygenator was first deoxygenated by purging with nitrogen gas (N2) to reduce dissolved oxygen levels to less than about 1% oxygen. An external measurement well was then attached to the frontend region of the device, and approximately 2.5 mL of 1 x phosphate-buffered saline (PBS) was added to define a controlled aqueous volume over the oxygenator. Under these conditions, the oxygenator was driven at an applied potential of about 1.8 V with an 80% duty cycle, using the same four devices that were characterized in Figure 6A, each operated for at least three days without shorts and with stable current output. Figure 6B shows the resulting dissolved oxygen profiles as a function of time, demonstrating that the coil CE configuration provides repeatable and predictable oxygenation curves across devices and runs. The average oxygen levels achieved with the coil CE are higher than those obtained in comparative devices employing an on-chip counter electrode, reflecting a significant improvement in performance in addition to the enhanced reliability and yield.Collectively, the oxygenation data in Figure 6B confirm that the coil counter electrode design effectively translates the stable current generation demonstrated in Figure 6A into robust and reproducible oxygen production, supporting its use to maintain adequate oxygen levels for high-density encapsulated cells within the implantable biohybrid system.Example 4 - Implantation and retrieval of capsules containing engineered cells

[0158] Figure 7A illustrates representative alginate capsules containing engineered ARPE-19 cells prior to loading into the implantable biohybrid device and implantation into a subject, e.g. primate. In one embodiment, single-layer alginate capsules having a target diameter of approximately 1500 pm are manufactured using a blend of 5% Z2A19-VLVG alginate and 3% SLG100 alginate at a 70:30 ratio. These single-layer capsules encapsulate ARPE-19 cells engineered to constitutively produce ipilimumab at a cell density of about 100*10A6 cells / mL within the capsule interior. In parallel, core-shell capsules are produced using the same alginate formulation and manufacturing methods, where the core contains polyclonal ARPE-19 cells engineered to constitutively produce human interleukin- 12 (hIL-12) at a cell density of about 50*10A6 cells / mL. The capsules are generally spherical and uniform in size, and the encapsulated cells appear evenly distributed within the gel matrix. For device loading, these ipilimumab-producing single-layer capsules and hIL-12-producing core-shell capsules areAttorney Docket No. 616146.100616introduced into the frontend cell chamber of the implantable device using sterile transfer pipettes. In a representative study, each device is loaded to near maximum capacity with approximately 1.8 mb of single-layer capsules and approximately 0.2 mL of core-shell capsules per device. Four devices are prepared in this manner for implantation. The loading process includes filling the chamber to its volumetric limit under sterile conditions, closing and securing the loading cap, and then storing the loaded devices in appropriate culture media until the time of surgery.Immediately prior to implantation, the devices are washed in normal saline to remove residual culture medium while maintaining sterility and capsule integrity. In one non-human primate, the maximum packed-capsule loading capacity of the device is about 2.4 mL per device; in other non-human primates, similar loading procedures are followed, with a maximum packed-capsule volume of approximately 2.0 mL per device. Figure 7A thus exemplifies the pre-implantation state of the manufactured capsules and their use in loading the devices to high cell densities suitable for in vivo biologic production.

[0159] Figure 7B depicts representative alginate capsules in the device retrieved at D60 postimplantable. In one embodiment, four devices loaded as described above — with approximately 1.8 mL of ipilimumab-producing single-layer capsules and approximately 0.2 mL ofhIL-12-producing core-shell capsules per device, for a total of about 2.0-2.4 mL of packed capsules depending on the subject — are implanted into non-human primates. The devices are introduced via a trocar or port, positioned within the peritoneal cavity, and left in place for an extended period while the encapsulated ARPE-19 cells produce the therapeutic biologies. During this time, the internal oxygenator subsystem of each device provides electrochemically generated oxygen to support the high-density encapsulated cell populations. Following the implantation interval, the devices are surgically retrieved, and the capsules are removed from the frontend cell chambers for inspection. As shown in Figure 7B, the retrieved capsules retain their overall spherical morphology and remain visually clean, with minimal adherent tissue or fouling, indicating that the chosen alginate formulation (5% Z2A19-VLVG blended with 3% SLG100), capsule size (-1500 pm), and device-level housing features are compatible with extended intraperitoneal residence and allow efficient retrieval of capsules. Figures 7A-7B thus demonstrate that production-scale manufacturing of composite single-layer and core-shell capsules at the stated cell densities, combined with loading to near-maximum packed volume (about 2.0-2.4 mL per device) using sterile transfer pipettes and standard handling (storage inAttorney Docket No. 616146.100616culture media and saline wash prior to implantation), yields devices that can be implanted, operated, and later explanted with recovery of structurally intact, clean capsules suitable for post-implant analysis.Example 5 - In-vivo Therapeutics Production

[0160] Figure 8A illustrates representative in vivo titers of ipilimumab in non-human primate (NHP) subjects implanted with the cell-based biohybrid devices described herein. Serum and intraperitoneal (IP) fluid samples were collected at multiple post-implantation time points between DO - D60, and ipilimumab concentrations were quantified by a plate-based enzyme-linked immunosorbent assay (ELISA). For each set of NHP samples, a dedicated assay plate was used, and all samples were run in triplicate to ensure analytical precision and reproducibility. All ipilimumab samples were assayed at a 1:30 dilution, with a lower limit of quantitation (LOQ) of approximately 10 ng / mL. The plotted data demonstrate that therapeutic levels of ipilimumab are achieved and maintained in vivo following implantation of the devices, with measurable titers observed in both serum and IP fluid over the course of the study. In addition, ipilimumab anti-drug antibodies (ADA) were evaluated in both serum and IP fluid using a corresponding ELISA format; no ADA directed against ipilimumab was detected in any of the tested samples. The absence of detectable ADA indicates that, under these conditions, the locally secreted ipilimumab did not elicit a measurable humoral anti-drug immune response in the NHPs, supporting the potential for sustained ipilimumab delivery from the encapsulated cell implants.

[0161] Figure 8B presents representative in vivo titers of human interleukin- 12 (hIL-12) produced by the implanted core-shell ARPE-19 cell capsules in non-human primate subjects. As with ipilimumab, serum and / or IP fluid samples were collected at multiple time points following implantation, and hIL-12 concentrations were determined using an ELISA specific for human IL-12. For each set of NHP samples, a single plate was used and all samples were run in triplicate to ensure consistency across replicates and animals. In contrast to the ipilimumab assay, the hIL-12 samples were run neat (undiluted) to maximize sensitivity, with a lower limit of quantitation of approximately 3.9 pg / mL. The data depicted in Figure 8B show that the encapsulated hIL-12-producing cells secreted quantifiable levels of hIL-12 in vivo, with titers exceeding the assay LOQ and demonstrating that the core-shell capsule component of the deviceAttorney Docket No. 616146.100616remained functional after implantation. The combination of the ipilimumab and hIL-12 titer profdes illustrated in Figures 8A and 8B confirms that the dual-product cell therapy system is capable of concurrently generating and sustaining systemic and / or local exposure to both a therapeutic antibody and a cytokine in the NHP model.Example 6- Biohybrid Device Function in NHP

[0162] Figure 9 illustrates representative in vivo functional data from non-human primates implanted with the retrievable biohybrid cell -based oxygenating devices described herein. The figure shows that operational device channels maintained stable wireless communication and steady oxygenator drive currents over an extended period of implantation, up to at least about 60 days. During this interval, individual oxygenator channels typically operated at currents of approximately 10-15 pA per channel under the programmed drive conditions. The recorded current traces show no evidence of progressive drift, intermittent failures, or abrupt changes suggestive of electrical shorts or open circuits. This stable electrical performance over weeks of implantation indicates that the electrode-tissue and electrode-electrolyte interfaces remained functional and that fouling and / or fibrotic responses in the peritoneal environment did not adversely affect oxygenator current delivery. Because the oxygen production rate is directly related to the applied current, the observed stability in current further supports that electrochemical oxygen generation within the device remained consistent throughout the implantation period, despite the expected foreign body response and tissue remodeling around the implant.

[0163] Figure 9 also depicts post-retrieval functional verification of the oxygenator subsystem following 60-90 days of in vivo operation. After retrieval of the devices from the non-human primates, the frontend cell chamber was opened, and the alginate capsules were removed and rinsed to expose the internal oxygenator components. The explanted devices were then placed in an aqueous electrolyte, and a drive voltage was applied to the oxygenator electrodes. Under these conditions, visible oxygen gas bubbles were observed emanating from the oxygenator region, confirming that the electrochemical oxygen generation function of the device was preserved after prolonged implantation. The presence of robust O2 bubbling upon application of a high drive voltage demonstrates that the working and counter electrodes, their encapsulated connections, and the backend electronics remained operational and capable ofAttorney Docket No. 616146.100616generating oxygen even after 60-90 days in vivo. Taken together with the stable in vivo current data, these post-retrieval observations support that the biohybrid device can maintain long-term oxygenator performance in the peritoneal environment, and that any fibrosis or fouling that developed during implantation did not irreversibly compromise oxygen generation capacity. Example 7- Device lifecycle

[0164] With reference to Fig. 10, a flow chart is shown that illustrates an intended lifecycle and use paradigm for a retrievable implantable biohybrid device. As depicted, the biohybrid device is first provided as a fully assembled and sterilized unit that includes a cell-containing chamber and an associated bioelectronic oxygenation subsystem. In some embodiments, the device is supplied in sterile packaging suitable for surgical handling, while a population of therapeutic, cell-laden capsules (for example, alginate capsules containing engineered ARPE-19 cells) is provided separately in a sterile syringe or vial. This separation facilitates independent manufacture, quality control, storage, and transport of the device hardware and the therapeutic cell product.

[0165] Figure. 10 further illustrates that, prior to use, the device and the cell-laden capsules are brought together in an aseptic environment, such as a surgical suite or cleanroom. The capsules are introduced into the device’s cell chamber via a loading port, and the chamber is then sealed, thereby entrapping the capsules within the frontend chamber of the biohybrid device. In some embodiments, device wake-up, initialization, and activation of the oxygenation function are accomplished wirelessly via a near-field communication (NFC or vNFC) interface, which may both power and configure the device prior to implantation. As schematically indicated, multiple biohybrid devices may optionally be prepared and communicatively linked in the surgical setting to coordinate dosing, such as by distributing a desired total cell load or therapeutic production capacity across several implants. In certain embodiments, when multiple devices are used, they can be attached together via suture hole / attachment holes on the frontend and backend chambers. For example, the multiple devise can be attached in a chain arrangement with the suture hole / attachment hole of the frontend chamber is attached to the suture hole / attachment hole of backend chamber of another device. In certain embodiments, the number of the device being implanted is determined based on the dosing requirement.Attorney Docket No. 616146.100616

[0166] As shown in Figure. 10, once loaded and activated, the device is implanted into a patient. In certain embodiments, the device is introduced through a laparoscopic port or trocar, for example of about 10-20 mm, such as about 15 mm, into the peritoneal cavity and is secured, for example by loosely suturing the suture hole / attachment hole / attachment hole to the abdominal or peritoneal wall. Following implantation, the device remains in situ for an intended therapeutic period, such as about 10-90 days, or 60-90 days, during which the encapsulated cells produce one or more therapeutic agents and the embedded oxygenation subsystem maintains local oxygen supply to support cell viability and function. At the conclusion of the treatment interval, Figure. 10 illustrates that the device is explanted and retrieved, for example via the same port and suture used for implantation. After retrieval, the device can be interrogated via NFC and / or otherwise tested to assess device operation, and the encapsulated cells and / or capsules can be subjected to post-explant analysis or characterization, thereby providing both therapeutic benefit during the implantation phase and actionable information regarding device and cell performance over the course of the implantation lifecycle.Example 8- Biomedical Materials with ZxAy molecules library[00167J In certain embodiments, the device comprises one or more biomedical materials with one or more ZxAy molecules. In certain embodiments, the device is coated with one or more biomedical materials with one or more ZxAy molecules.

[0168] In certain embodiments, the ZxAy molecule is Z2A19, whose stricture is shown in Fig. 12A. Z1A19 is disclosed in US patent publications US20240301093A1, which is incorporated references. In certain embodiments, all ZxAy molecules library can be coupled to biomedical materials (BioMed Clear) due to similarity in structure.

[0169] Fig. 12A shows chemical structure of Z2A19. Fig. 12B shows surface characterization ofZ2A19 by XPS.

[0170] Coating Solution Preparation

[0171] In certain embodiments, a coating solution is prepared by dissolving Z2A19 in a minimal amount of water to form a concentrated aqueous solution, which is then added to acetonitrile to provide a mixed solvent system. The concentration of Z2A19 in the resulting coating solution is adjusted to a target concentration of about 0.1 M, with acceptable concentrations ranging from about 0.05 M to about 1.5 M. After Z2A19 is fully solubilized in theAttorney Docket No. 616146.100616acetonitrile-containing medium, nitrogen gas is bubbled through the solution for at least 30 minutes to deoxygenate and condition the solution. While nitrogen bubbling is maintained, triethylamine is introduced into the solution at a stoichiometry of approximately 1.3 molar equivalents relative to Z2A19, with a permissible range of from about 1.0 to about 1.5 molar equivalents, thereby forming a reactive coating bath suitable for surface treatment of BioMed Clear parts.

[0172] Coating of BioMed Clear Parts (biomedical materials)

[0173] In some embodiments, BioMed Clear parts are first fabricated by an additive manufacturing or other printing process and then subjected to a post-print cleaning and coating procedure. Immediately after printing, the parts are washed in isopropyl alcohol for approximately 10 minutes with agitation sufficient to remove uncured resin from all exposed surfaces. Following this washing step, the parts are briefly dried with air to remove excess solvent, and the dried parts are then submerged in the previously prepared Z2A19-containing coating solution. While immersed in the coating solution, the parts are maintained at a temperature of about 40 °C to about 45 °C, for example on a rocking plate or under another form of gentle mixing, for a period of approximately 4 hours, with an acceptable deviation of ±15 minutes, to allow the coating to form and / or react with the substrate surface.

[0174] At the conclusion of the coating period, the parts are removed from the coating solution and immediately transferred to a bath of fresh acetonitrile, in which they are submerged for about 3 minutes with gentle agitation to remove unbound coating solution. This acetonitrile wash step may be repeated to further reduce residual reactants or by-products. The parts are then submerged in distilled water for about 3 minutes with gentle agitation, and this aqueous wash is likewise repeated to complete the removal of solvent and soluble residues. After washing, the parts are dried under a nitrogen stream for approximately 10 minutes and subsequently degassed under low vacuum conditions for about 20 minutes to evacuate trapped gases and residual volatiles. The dried and degassed parts are then subjected to a UV curing step, in which they are exposed to light having a wavelength in the range of approximately 354 nm to 405 nm for about 30 minutes to initiate and / or complete crosslinking or surface fixation of the coating. Following UV curing, the parts undergo a thermal curing step in an oven at a temperature of about 55 °C to about 65 °C for a duration of approximately 90 to 120 minutes, thereby stabilizing the coating and providing a finished, modified BioMed Clear surface.Attorney Docket No. 616146.100616

[0175] As shown in Fig. 12B, increase in surface nitrogen and sulfur indicate successful covalent attachment Z2A19 to BioMed Clear resin.Summary

[0176] In some embodiments, a fully assembled and sterilized implantable device is provided that comprises all components of a biohybrid therapeutic system, including a front-end cell chamber and oxygenation subsystem, a backend electronics and power subsystem, and one or more mechanical attachment features. The front end of the device includes a mechanically locking cap configured to be secured over a loading port. During preparation for use, encapsulated ARPE-19 cells contained in alginate spheres are injected into the device through the loading port, and the mechanically locking cap is placed and secured, thereby entrapping the alginate spheres within an internal cage or chamber structure. The capsules may comprise core or core-shell alginate spheres with ARPE-19 cells that constitutively produce Ipilbimab and / or IL-12, for example at a cell loading density of about 100 million cells per milliliter (100M cells / mL). In some embodiments, dose escalation is achieved by “daisy chaining” multiple devices together, such as by suturing up to three devices together via suture holes / attachment holes on their front and / or back ends. In another embodiment, up to 4, 5, 6, 7, 8, 9, or 10 device can be suture together in a chain. The loaded device, or daisy-chained devices, is then introduced into the peritoneal space of an animal or human subject through a port, such as a laparoscopic trocar of about 15 mm diameter. Once in the intraperitoneal space, the device is loosely sutured using a single suture hole / attachment hole located at an end of the device opposite the loading port, with the suture attached to a wall of the peritoneal cavity such that the device hangs and retains rotational freedom. After completion of a treatment period, the device can be retrieved from the peritoneal space, for example via the same or a similar minimally invasive access route.

[0177] The device is configured to maintain high-density allogeneic cells in a viable state within a retrievable form factor for extended durations, for example about 9-12 weeks, when implanted in the intraperitoneal space. During this period, the device functions as an implantable bioreactor in which encapsulated ARPE-19 cells engineered to produce IL-12 and Ipilbimab secrete one or more biologic agents into the surrounding environment. The front end of the device houses both the oxygenation subsystem and the cell capsules, and includes an oxygenator chip configured to electrochemically generate oxygen in proximity to the encapsulated cells. The oxygenator chip can be operated in either a constant-current mode or a constant-voltage mode byAttorney Docket No. 616146.100616applying a controlled current (I) or voltage (V), respectively, to oxygenator contact pads referenced to an on-chip counter electrode. The oxygenation chip is electrically and mechanically coupled to a printed circuit board and battery assembly contained within a hermetic enclosure, such as a sealed can or cylindrical housing, through one or more hermetic feedthroughs that maintain fluid isolation of the electronics while allowing electrical connection.

[0178] The hermetically enclosed electronics subsystem may include commercial off-the-shelf components such as a microcontroller and a communications integrated circuit, which together implement a miniature potentiostat architecture for controlling and monitoring the oxygenator. In operation, the electronics apply and measure current and / or voltage to the oxygenator chip according to programmed control algorithms. On-board firmware is configured to provide stable supply currents and / or voltages within predetermined safety bounds and to control duty cycling of the oxygenator to balance oxygen delivery, power consumption, and byproduct generation. The firmware may further monitor oxygenator current, battery status, and other operational parameters, and store corresponding data in on-board memory for later retrieval, for example after device explantation or during authorized communication sessions. An antenna is provided to enable wireless communication using, for example, Bluetooth Low Energy (BLE) and / or near-field communication (NFC) protocols. In some implementations, a very near field communication (vNFC) mode is employed to limit communication range to millimeter-scale distances, such that communication for device release, configuration, and post-retrieval data collection is only possible when a reader is placed in close proximity to the device. The communication system is configured such that communication is not possible through tissue when the device is implanted in the intraperitoneal space, and standard encryption techniques are employed to secure NFC-based data exchange.

[0179] Prior to implantation in human subjects, the device can be configured to operate in an autonomous mode in which the control of the voltage applied to the oxygenator is dynamically adjusted in response to measured oxygenator current. In such embodiments, the on-board firmware processes current measurements and increases or otherwise modulates the applied voltage up to a predefined safety threshold, which may be set based on known limits for electrochemical byproduct production and the onset potential for oxygen evolution. This closed-loop or semi-closed-loop control enables the device to adapt oxygen generation to the needs of the encapsulated high-density allogeneic cells while remaining within safe operatingAttorney Docket No. 616146.100616limits. In combination, the encapsulated, engineered ARPE-19 cells, the oxygenation chip, the hermetically sealed power and control electronics, and the retrievable mechanical form factor provide an implantable, controllable, and data-enabled platform for sustained intraperitoneal delivery of biologic therapeutics such as IL-12 and Ipilbimab over clinically relevant timeframes.

[0180] 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.

[0181] 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.

[0182] 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

Attorney Docket No. 616146.100616CLAIMSWhat is claimed is:

1. A retrievable implantable biohybrid system housing engineered cells for producing therapeutics in a subject, comprising:a frontend chamber housing engineered cells which are configured to produce at least one therapeutics;a backend chamber housing at least one electronic component; wherein a first end of the backend chamber is hermetically connected to the frontend chamber; anda retrievable attachment having an attachment hole, wherein the retrievable attachment is connected to a second end of the backend chamber.

2. The retrievable implantable biohybrid system according to claim 1, wherein the attachment hole is configured to be attached to an internal surface of a cavity inside the subject via an attaching mean.

3. The retrievable implantable biohybrid system according to claim 2, wherein the cavity is the peritoneal cavity.

4. The retrievable implantable biohybrid system according to claim 3, wherein the attaching mean comprises suture.

5. The retrievable implantable biohybrid system according to claim 1, wherein the frontend chamber comprises a support cage having an internal chamber for housing capsules containing the engineered cells.

6. The retrievable implantable biohybrid system according to claim 5, wherein the support cage having a loading port configured to receive the capsules containing the engineered cells.Attorney Docket No. 616146.1006167. The retrievable implantable biohybrid system according to claim 6, wherein the frontend chamber further comprising a loading cap configured to engage with the loading port.

8. The retrievable implantable biohybrid system according to claim 5, wherein the support case having multiple therapeutic holes which are configured to permit therapeutics produced by the engineered cells passing therethrough.

9. The retrievable implantable biohybrid system according to claim 8, wherein each of the multiple therapeutic holes has a diameter of about 1 mm.

10. The retrievable implantable biohybrid system according to claim 5, wherein the support cage is made of a biomedical material, wherein the biomedical material comprises one or more of small-molecule-modified biomedical material, medical-grade liquid silicone rubber elastomer, polyetheretherketone (PEEK), polyurethane, polyethylene terephthalate (PET), and polycarbonate.

11. The retrievable implantable biohybrid system according to claim 5, wherein an oxygenator is disposed inside the frontend chamber for producing oxygen.

12. The retrievable implantable biohybrid system according to claim 5, wherein the frontend chamber further comprises a frontend attachment hole.

13. The retrievable implantable biohybrid system according to claim 12, wherein the backend chamber comprises a hermetic cannister body and two hermetic cannister ends forming a hermetic chamber.

14. The retrievable implantable biohybrid system according to claim 13, wherein a mechanical assembly support is disposed inside the hermetic chamber.Attorney Docket No. 616146.10061615. The retrievable implantable biohybrid system according to claim 13, wherein the at least one electronic component is disposed inside the hermetic chamber.

16. The retrievable implantable biohybrid system according to claim 15, wherein one of the two hermetic cannister ends is the first end and comprises at least one chip-hermetic feedthrough connector.

17. The retrievable implantable biohybrid system according to claim 16, wherein the oxygenator and the at least one electrical component are in communication via the at least one chip-hermetic feedthrough connector.

18. The retrievable implantable biohybrid system according to claim 13, wherein the retrievable attachment and the second end of the backend chamber forms an attachments chamber which is configured to house at least one antenna.

19. The retrievable implantable biohybrid system according to claim 18, wherein the retrievable attachment is made of the biomedical material.

20. The retrievable implantable biohybrid system according to claim 18, wherein the attachment hole having a diameter of about 2 mm and locates in in adjacent to a center of a free end of the retrievable attachment opposite to an end connected to the second end of the backend chamber.

21. The retrievable implantable biohybrid system according to claim 1, wherein the retrievable implantable biohybrid system has a diameter less than about 1.5 mm and a length less than about 6 cm.

22. A treatment procedure for delivering therapeutics to a subject, comprising:obtaining one or more capsules housing engineered cells and one or more retrievable biohybrid devices;loading the one or more capsules into the one or more retrievable biohybrid device;Attorney Docket No. 616146.100616delivering the one or more retrievable biohybrid device into an internal cavity of a subject;attaching the one or more retrievable biohybrid device to a wall of the internal cavity of the subject.

23. The procedure of claim 22 further comprising:removing the one or more retrievable biohybrid device from the subject after a treatment period.

24. The procedure of claim 23, wherein the treatment period ranges between about 10-90 days.

25. The procedure of claim 24, wherein the engineered cells produce one or more therapeutics during the treatment period.

26. The procedure of claim 23, wherein the one or more retrievable biohybrid device comprises multiple retrievable biohybrid device; wherein the multiple retrievable biohybrid device are attached to each other.

27. The procedure of claim 23, wherein each of the one or more retrievable biohybrid devices comprises a frontend chamber configured to house the one or more capsules, a backend chamber configured to house one or more electronic components.

28. The procedure of claim 27, wherein the frontend chamber configured to house the one or more capsules and comprises an oxygenator, a backend chamber configured to house one or more electronic components; wherein the oxygenator is electronically connected to the one or more electronic components.

29. The procedure of claim 27, wherein at least one of the frontend chamber and the backend chamber comprises an attachment hole, wherein the one or more retrievableAttorney Docket No. 616146.100616biohybrid device are attached to the wall of the internal cavity of the subject via the attachment hole.

30. The procedure of claim 25, wherein the one or more therapeutics treats a medical condition of the subject.

31. The procedure of claim 30, wherein the internal cavity is the peritoneal cavity of the subject.

32. The procedure of claim 30, wherein the subject is a human or a non-human mammal.

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