Biopower pharmaceutical device

Abstract

Biopower pharmaceutical devices are provided. The biopower pharmaceutical devices include a cell reservoir configured to house a cell cluster, the cell cluster including organoids fused with biological material; and a cell controller configured to control the organoids in the cell cluster to secrete active ingredients using electrical signals.

Description

[0001] This application claims the benefit of Korean Patent Application No. 10-2020-0005729, filed on January 16, 2020, with the Korean Intellectual Property Office, the entire disclosure of which is incorporated herein by reference for all purposes. Technical Field

[0002] The following description relates to bioelectric pharmaceutical devices that utilize cell clusters. Background Technology

[0003] An artificial pancreas can be an artificial organ created for the purpose of treating diabetes and can be used as an islet in the pancreas. For example, islets from the same or different species of animals can be sealed in a semi-permeable membrane to prevent immune rejection and can be implanted into the body. Summary of the Invention

[0004] The present invention is provided in a simplified form to describe the selection of concepts further described in the following detailed description. This summary is not intended to identify key or essential features of the claimed subject matter, nor is it intended to help determine the scope of the claimed subject matter.

[0005] In one general aspect, a bioelectric pharmaceutical device includes: a cell reservoir configured to contain a cluster of cells, the cluster including organoids fused with biomaterial; and a cell controller configured to use electrical signals to control the secretion of active ingredients from the organoids in the cell cluster.

[0006] Cell clusters can be contained in cell reservoirs, and the cell clusters may include hydrogels and β-cell organoids disposed within the hydrogels.

[0007] The device may include an electrochemical sensor configured to sense a target molecule, wherein, in order to control secretion, the cell controller may be configured to regulate the rate of production of the active ingredient of the organoid in the cell cluster based on the result of sensing the target molecule.

[0008] In order to sense target molecules, electrochemical sensors can be configured to sense another electrical signal generated by the reaction between the target molecule and an enzyme.

[0009] To control secretion, the cell controller can be configured to perform one or both of the following based on the sensed concentration of the target molecule: applying electrical stimulation that promotes the secretion of organoid active ingredients in the cell cluster; and interrupting the electrical stimulation.

[0010] Interrupting electrical stimulation may involve either reducing the level of electrical stimulation or terminating the application of electrical stimulation, or both.

[0011] To control secretion, the cell controller can be configured to: identify the body's metabolic state based on the concentration of the sensed target molecule; and determine whether to apply electrical stimulation to the cell cluster based on the identified metabolic state.

[0012] In order to sense the target molecule, the electrochemical sensor can be configured to: sense the altered concentration of the target molecule in response to organoids in the cell cluster secreting an active ingredient at a regulated rate of active ingredient production based on electrical stimulation; and in order to control the secretion, the cell controller can be configured to: re-identify the metabolic state based on the altered concentration; and re-determine whether to apply electrical stimulation to the cell cluster based on the re-identified metabolic state.

[0013] To control secretion, the cell controller can be configured to: apply electrical stimulation to the cell cluster that promotes the secretion of organoid active ingredients in the cell cluster in response to a sensed concentration level of the target molecule within a first range; and interrupt the electrical stimulation to the cell cluster in response to a sensed concentration level of the target molecule within a second range.

[0014] The electrochemical sensor can be configured to sense the body’s blood glucose level, and in order to control secretion, the cell controller can be configured to apply electrical stimulation to the cell cluster that promotes the secretion of insulin by organoids in the cell cluster in response to the sensed blood glucose level exceeding a threshold level.

[0015] The active ingredient may include insulin, and the target molecule may include blood glucose.

[0016] To control secretion, the cell controller can be configured to: generate a target generation rate based on the result of sensing the target molecule to determine the rate of generation of the active ingredient; and determine any one or any combination of the pulse width, magnitude, frequency, phase, and waveform of an electrical signal based on the determined target generation rate, wherein the electrical signal is applied to the cell cluster.

[0017] To control secretion, the cell controller can be configured to determine the frequency of an electrical signal to be within any one of the β band, the γ band including 40 Hz, and the peak band exceeding 400 Hz, and apply the electrical signal to the cell cluster.

[0018] The device may include: a control channel electrode configured to apply an electrical signal to a cell cluster; an active ingredient channel electrode disposed between the cell cluster and a blood vessel; and a body channel electrode configured to apply another electrical signal to the blood vessel.

[0019] The cell controller can be configured to promote the regeneration of capillaries adjacent to the bioelectric pharmaceutical device using active ingredient channel electrodes and body channel electrodes in response to the bioelectric pharmaceutical device being in implantation mode.

[0020] To control secretion, the cell controller can be configured to: in response to the bioelectric pharmaceutical device being in a therapeutic mode, apply electrical signals to the cell clusters by using control channel electrodes to promote the secretion of active ingredients by organoids in the cell clusters.

[0021] The active ingredient can be expelled to the outside of the bioelectric pharmaceutical device and bind to an ion transporter, and the cell controller can be configured to induce the active ingredient to move into the blood vessel by applying another electrical signal to the outside of the bioelectric pharmaceutical device through an active ingredient channel electrode in response to the bioelectric pharmaceutical device being in a therapeutic mode.

[0022] In order to apply the other electrical signal to the outside of the bioelectric pharmaceutical device, the cell controller may be configured to form an electrical path between the blood vessel and the active ingredient channel electrode by applying one of direct current (DC) stimulation and alternating current (AC) stimulation to the active ingredient channel electrode.

[0023] The cell reservoir can be configured to be detachable from the cell controller.

[0024] The cell storage device may include a loading port configured to receive an injection of additional cell clusters from outside the bioelectric pharmacy device.

[0025] The cell reservoir can be configured to house an electrochemical sensor and may include electrodes disposed outside the cell reservoir for electrical connection to a cell controller.

[0026] In another general aspect, a bioelectric pharmaceutical device includes: an electrochemical sensor configured to sense a target molecule in vivo; a cell reservoir configured to contain a cluster of cells, the cluster including organoids disposed in biomaterial; and a cell controller configured to apply an electrical signal to the cell cluster to induce the organoids to secrete an active ingredient based on the result of sensing the target molecule.

[0027] In another general aspect, a processor implementation method for a bioelectric pharmaceutical device includes: sensing a concentration level of a target molecule using an electrochemical sensor disposed in a cell reservoir; determining a target generation rate of an active ingredient secreted by an organoid disposed in the cell reservoir based on the concentration level; determining an electrical signal to be applied to the organoid based on the target generation rate; and applying the electrical signal to the organoid to induce the secretion of the active ingredient at the target generation rate.

[0028] A non-transitory computer-readable storage medium stores instructions that, when executed by a processor, configure the processor to perform the method.

[0029] Other features and aspects will become clear from the following detailed description, drawings, and claims. Attached Figure Description

[0030] Figure 1 An example of a bioelectric pharmaceutical device is shown.

[0031] Figure 2 An example of a bioelectric pharmaceutical device is shown.

[0032] Figure 3 Examples of cell cluster culture, implantation of bioelectric pharmaceutical devices, and treatment using cell clusters are shown.

[0033] Figure 4 An example is shown in which an active ingredient is secreted by organoids in a cell cluster via electrical stimulation in a bioelectric pharmaceutical device.

[0034] Figures 5A to 5C An example of an electrochemical sensor for a bioelectric pharmaceutical device is shown.

[0035] Figure 6 and Figure 7 An example of electrical stimulation applied to a cell cluster via a bioelectric pharmaceutical device is shown.

[0036] Figure 8 An example of an electrode channel in a bioelectric pharmaceutical device is shown.

[0037] Figure 9 An example of an implantation procedure performed via a bioelectric pharmaceutical device is shown.

[0038] Figure 10 An example of the operation of the bioelectric pharmaceutical device in therapeutic mode is shown.

[0039] Figure 11 An example is shown of promoting the absorption of active ingredients through a bioelectric pharmaceutical device.

[0040] Figure 12 An example of the overall structure of a bioelectric pharmaceutical device is shown.

[0041] Figure 13 An example of the application of a bioelectric pharmaceutical device is shown.

[0042] Figure 14 and Figure 15 An example of the structure of a cell delivery system that can be separated from a bioelectric pharmaceutical device is shown.

[0043] Figure 16 An example of a method for secreting active ingredients using a bioelectric pharmaceutical device is shown.

[0044] Throughout the accompanying drawings and detailed embodiments, unless otherwise described or provided, the same reference numerals will be understood to denote the same elements, features, and structures. The drawings may not be to scale, and for clarity, illustration, and convenience, the relative dimensions, scale, and depiction of elements in the drawings may be exaggerated. Detailed Implementation

[0045] The following detailed embodiments are provided to aid the reader in gaining a comprehensive understanding of the methods, apparatus, and / or systems described herein. However, various changes, modifications, and equivalents of the methods, apparatus, and / or systems described herein will become apparent upon understanding this disclosure. For example, the order of operations described herein is merely illustrative and is not limited to those orders set forth herein, but may be changed as will become clear upon understanding this disclosure, except for operations that must occur in a specific order. Furthermore, for clarity and conciseness, descriptions of features known in the art may be omitted.

[0046] The features described herein may be implemented in different forms and are not to be construed as limited to the examples described herein. Rather, the examples described herein have been provided merely to illustrate some of the many feasible ways of implementing the methods, apparatus, and / or systems described herein that will be clear upon understanding the disclosure of this application.

[0047] The terminology used herein is for the purpose of describing particular examples only and is not intended to limit disclosure. As used herein, the singular form is intended to include the plural form as well, unless the context clearly indicates otherwise. As used herein, the term "and / or" includes any one of the related listed items and any combination of any two or more. As used herein, the terms "comprising," "including," and "having" indicate the presence of the stated features, quantities, operations, elements, components, and / or combinations thereof, but do not exclude the presence or addition of one or more other features, quantities, operations, elements, components, and / or combinations thereof.

[0048] Throughout the specification, when an element (such as a layer, region, or substrate) is described as being "on" another element, "connected to," or "bonded to" another element, the element may be directly "on" said other element, "connected to," or "bonded to" said other element, or there may be one or more other elements in between. Conversely, when an element is described as being "directly on" another element, "directly connected to," or "directly bonded to" another element, there may be no other elements in between. Similarly, expressions such as "between" and "immediately between," and "adjacent" and "closely adjacent" may be interpreted as described above.

[0049] Unless otherwise defined, all terms used herein (including technical and scientific terms) shall have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains, and as commonly understood after understanding this disclosure. Unless expressly defined herein, terms (such as those defined in a general dictionary) shall be interpreted as having a meaning consistent with their meaning in the context of the relevant field and in this disclosure, and shall not be interpreted in an idealized or overly formal sense. The use of the term “may” (e.g., what an example or embodiment may include or implement) in connection with examples or embodiments indicates the existence of at least one example or embodiment that includes or implements such a feature, but not all examples are limited thereto.

[0050] In the following description, examples will be described in detail with reference to the accompanying drawings. The specific structural or functional descriptions below are merely illustrative, and the scope of the examples is not limited to the descriptions provided in this specification. The same reference numerals in the drawings denote the same elements, and functions or configurations known to those skilled in the art after understanding this disclosure may be omitted herein.

[0051] Various modifications can be made to the examples. Here, the examples are not to be construed as limited to what is publicly available, but should be understood to include all modifications, equivalents, and substitutes within the scope of the publicly available ideas and techniques.

[0052] When describing the examples with reference to the accompanying drawings, the same reference numerals denote the same constituent elements, and repetitive descriptions associated with them will be omitted. In the description of the examples, descriptions of related structures or functions will be omitted where such descriptions would lead to a vague interpretation of this disclosure.

[0053] Figure 1 An example of a bioelectric pharmaceutical device 100 is shown.

[0054] Reference Figure 1 The bioelectric pharmaceutical device 100 may include a cell cluster 110 and a cell controller 120.

[0055] Cell cluster 110 may include organoids embedded in biological material and may correspond to the fusion of organoids and biological material. Organoids may be cells capable of generating active ingredients in a three-dimensional (3D) structure and may be a group of cells cultured and differentiated from stem cells in an in vitro environment. For example, organoids may be represented as aggregates or spheroids.

[0056] An active ingredient can refer to a substance that has pharmacological activity in the diagnosis, treatment, relief, cure, or prevention of a disease, or influencing the physiological functions of the human body. In the following description, an active ingredient can be a substance with pharmacological activity affecting the physiological functions of the human body, and an active ingredient can be insulin. Insulin can be a substance that treats, relieves, cures, or prevents diabetes. However, active ingredients are not limited to insulin, and the following description applies to other active ingredients as well.

[0057] When the bioelectric pharmaceutical device 100 is designed to secrete insulin as an active ingredient, the cell cluster 110 may include β-cell organoids embedded in a hydrogel as a biomaterial. The β-cell organoids may be a large number of cells including at least one precursor corresponding to the final stage or a stage preceding the final stage of pancreatic β-cell differentiation. However, the cell cluster 110 including β-cell organoids is not limited and may also include other cells or substances. For example, the cell cluster 110 may include both α-cell organoids and β-cell organoids. However, the examples are not limited thereto; the cell cluster 110 may also include components for improving the efficiency and survival rate of each cell. Furthermore, the cell cluster 110 may also include additional factors for the stability of the organoids. These additional factors may be, for example, a culture medium.

[0058] In one example, cell cluster 110 may primarily comprise organoids of predetermined cells. Cell cluster 110 may include a greater number of organoids of predetermined cells than organoids of other cells. For example, cell cluster 110 may include β-cell organoids, or may include any one or any combination of α (alpha) cell organoids, δ (delta) cell organoids, and other pancreatic cells and β-cell organoids. In this example, cell cluster 110 may have a cell ratio different from that of the islets of Langerhans. For example, the ratio of β-cell organoids to organoids included in cell cluster 110 may be greater than or equal to a threshold ratio. For example, the percentage of β-cell organoids in cell cluster 110 may be greater than or equal to 85%. The example is not limited to this; the percentage of β-cell organoids in cell cluster 110 may be greater than or equal to 90%.

[0059] Furthermore, the cell cluster 110 can be in an injectable form. When the biomaterial is a hydrogel, the cell cluster 110, in which the hydrogel and organoid are fused, can be injected via a flow path. Therefore, the cell cluster 110 can be replenished by injection, and non-limiting examples will be referenced below. Figure 14 Describe it.

[0060] Cell controller 120 can control the secretion of active ingredients from organoids in cell cluster 110 by applying electrical signals to cell cluster 110. For example, cell controller 120 can control cell cluster 110 by controlling sensing and stimulation channels. Cell controller 120 can promote the production of active ingredients from organoids in cell cluster 110 by applying electrical stimulation to cell cluster 110 via electrodes of stimulation channel. Cell controller 120 can obtain the result of sensing target molecules via electrodes of sensing channel through electrochemical sensors, and can adjust the production rate of active ingredients from organoids in cell cluster 110 based on the result. The following will refer to Figure 2 , Figure 5A , Figure 5B and Figure 5C Describe non-limiting examples of electrochemical sensors.

[0061] As described above, the cell controller 120 can use and determine information obtained via the sensing channel of the control channel through the electrochemical sensor, and control the cell cluster 110 via the stimulation channel of the control channel. Therefore, the bioelectric pharmaceutical device 100 can regulate the secretion of an active ingredient based on the amount of the target molecule when operating as a closed-loop system. By regulating the secretion of the active ingredient, the amount of the target molecule in the body can also be regulated.

[0062] Figure 2 An example of a bioelectric pharmaceutical device 200 is shown.

[0063] Reference Figure 2 The cell controller 220 may include a channel switch 221, a stimulator 222, a processor 223 (e.g., one or more processors), an electrochemical sensor 224, a power manager 225, a battery 226, an energy harvester 227, and a communicator 228.

[0064] Channel switch 221 can switch the connection to the channel electrode that applies and receives electrical signals. When stimulator 222 and electrochemical sensor 224 are operating, channel switch 221 can change the connection to the electrode (e.g., working electrode, reference electrode, or counter electrode) electrically connected to the control channel disposed in or adjacent to cell cluster 210 for each operating mode. In one example, cell controller 220 can use channel switch 221 to connect the electrode of the sensing channel to electrochemical sensor 224 to measure the amount of a target molecule. In another example, cell controller 220 can use channel switch 221 to connect the electrode of the stimulating channel to stimulator 222 to secrete an active ingredient via organoids in cell cluster 210. However, the channel including the electrode is not limited to this.

[0065] The stimulator 222 can apply an electrical signal determined by the processor 223 to the electrodes of the stimulation channel. For example, the stimulator 222 can apply an electrical signal with amplitude, magnitude, frequency, phase, and waveform determined by the processor 223 to the stimulation channel. For example, the electrodes of the stimulation channel can be positioned adjacent to the cell cluster 210 to provide an electrical signal to the cell cluster 210.

[0066] Electrochemical sensor 224 can electrochemically sense target molecules. For example, electrochemical sensor 224 may be or may include a transducer, and may include a substance (e.g., an enzyme) that chemically reacts with the target molecule to generate electricity, and may include an electrode to which the substance is applied (i.e., in contact with or connected to the substance). However, electrochemical sensor 224 is not limited thereto. In one example, cell controller 220 may use electrochemical sensor 224 to electrochemically monitor the concentration of target molecules in vivo. As a non-limiting example, reference will be made below. Figure 5A , Figure 5B and Figure 5C Further description of electrochemical sensor 224.

[0067] Processor 223 controls channel switch 221, stimulator 222, electrochemical sensor 224, and power manager 225. Furthermore, processor 223 can identify the body's metabolic state based on the sensing results of target molecules and control the operation of each component based on the identified metabolic state. For example, processor 223 can identify the metabolic state based on the concentration of target molecules and determine whether to apply electrical stimulation to cell cluster 210 based on the identified metabolic state. Metabolic states can be categorized based on the amount, concentration, and / or level of target molecules contained in the body and can include, for example, states requiring the input of active ingredients (e.g., processor 223 can determine states requiring the input of active ingredients) and states not requiring the input of active ingredients (e.g., processor 223 can determine states preventing the input of active ingredients). Figure 13 As shown, the target molecule can be blood glucose, and the body's metabolic state can be classified as, for example, hyperglycemia, normal state, or hypoglycemia.

[0068] Power manager 225 manages the power supply to cell controller 220. For example, power manager 225 can use the power generated by energy harvester 227 to charge battery 226. Power manager 225 can use the power stored in battery 226 to operate other modules (e.g., channel switch 221, stimulator 222, processor 223, or electrochemical sensor 224). Furthermore, power manager 225 can use the power generated by energy harvester 227 to operate cell controller 220.

[0069] Battery 226 can store power for operating cell controller 220.

[0070] Energy harvester 227 can generate electricity in response to an external signal. For example, in response to receiving a signal that oscillates through a medium (e.g., an ultrasonic signal or an electromagnetic wave signal), energy harvester 227 can use a piezoelectric element to generate electricity.

[0071] The communicator 228 can establish wireless communication with an external device. For example, the communicator 228 can transmit signals to or receive signals from an external device via wireless communication. The communicator 228 can transmit information collected by the bioelectric pharmaceutical device 200 (e.g., information associated with the concentration of the target molecule) and information associated with the operation of the bioelectric pharmaceutical device 200 (e.g., pulses and timing of electrical stimulation for drug secretion) to the external device. Furthermore, the communicator 228 can receive control signals for the bioelectric pharmaceutical device 200 from the external device. In one example, the processor 223 can control the channel switch 221, the stimulator 222, the electrochemical sensor 224, and / or the power manager 225 based on the received control signals.

[0072] Therefore, the bioelectric pharmaceutical device 200 can enhance the efficiency of cell cluster 210 and improve therapeutic effects by activating organoid secretory active ingredients in cell cluster 210 using cell controller 220.

[0073] Figure 3 Examples of implantation of bioelectric pharmaceutical devices and treatment using cell clusters are shown.

[0074] Cell cluster 313 may be a 3D structure in which organoids 312 and biological material are fused. Organoids may be 3D cell aggregates including cells specific to a model organ (e.g., pancreas) (e.g., β cells). Organoids 312 may differentiate from stem cells 311 and may include, for example, β cell organoids.

[0075] Organoid 312 may correspond to a 3D cell mass having any or any combination of structures, cellular components, and functions similar to those of a living organ, and may be used as an artificial organ when biosimilarity is enhanced through implantation. For example, cell cluster 313 may comprise a fully implanted organoid 312. β-cell organoids may be, for example, cell aggregates comprising at least one β-cell precursor or at least one β-cell.

[0076] For example, to improve cell survival, cell cluster 313 may include activating factors and biomaterials fused with cell aggregates. However, the examples are not limited to biomaterials and activating factors, and cell cluster 313 may include other materials for improving the survival, stability, and effectiveness of β-cell organoids.

[0077] The cell controller 320 can enhance the secretion capacity of organoid active ingredients in the cell cluster 313 using electrochemical sensing and electrical stimulation as described above. However, the operation of the cell controller 320 is not limited to therapeutic modes, and the cell controller 320 can also play a role in the survival of the cell cluster 313.

[0078] Figure 4 An example is shown in which an active ingredient is secreted by organoids in a cell cluster via electrical stimulation in a bioelectric pharmaceutical device.

[0079] The cell controller 420 can regulate the rate of production of the active ingredient of organoids in the cell cluster 410 based on the result of sensing the target molecule 451. For example, the cell controller 420 can apply electrical stimulation to the cell cluster 410 to promote the secretion of the active ingredient by organoids in the cell cluster 410 based on the sensed concentration of the target molecule 451, or it can interrupt (e.g., stop or reduce) the electrical stimulation to the cell cluster 410.

[0080] like Figure 4 As shown, the electrodes of stimulation channel 422 (stimulation working electrode STIM_WE and stimulation counter electrode STIM_CE) and the electrodes of sensing channel 421 (sensing counter electrode EC_CE, sensing working electrode EC_WE, and sensing reference electrode EC_RE) are connected to cell controller 420. These electrodes may be electrically connected to cell cluster 410 and / or adjacent cell clusters 410. For example, the electrodes STIM_WE and STIM_CE of stimulation channel 422 and the electrodes EC_CE, EC_WE, and EC_RE of sensing channel 421 may be disposed in a cell reservoir 419 that accommodates (e.g., contains or surrounds) cell cluster 410. The electrodes of stimulation channel 422 and sensing channel 421 may be externally isolated from the bioelectric pharmaceutical device or from other components of the bioelectric pharmaceutical device.

[0081] Cell controller 420 can use the electrodes of sensing channel 421 to sense target molecule 451 introduced into cell reservoir 419. Electrochemical sensor can sense the electrical signal generated by the chemical reaction between target molecule 451 and an enzyme applied to the sensing working electrode EC_WE; a non-limiting example of the electrochemical sensor will be referred to below. Figures 5A to 5C Further description. The cell controller 420 can determine the concentration of the target molecule 451 in the cell reservoir 419 based on the magnitude of the electrical signal (e.g., voltage or current) generated by the chemical reaction. For example, the concentration of the target molecule 451 in the cell reservoir 419 can correspond to the concentration of the target molecule 451 in vivo.

[0082] Cell controller 420 can apply electrical signals to cell cluster 410 via electrodes STIM_WE and STIM_CE of stimulation channel 422. For example, cell controller 420 can apply electrical signals from stimulation working electrode STIM_WE to stimulation counter electrode STIM_CE via at least one cell cluster 410 through the electrode channel. Organoids in cell cluster 410 stimulated by the electrical signals can secrete active ingredient 452. For example, in response to stimulation, organoids in cell cluster 410 can secrete active ingredient 452 at an increased generation rate compared to before stimulation. Active ingredient 452 secreted by organoids in cell cluster 410 can be discharged from cell reservoir 419.

[0083] In one example, cell controller 420 may determine the target generation rate based on the result of sensing target molecule 451, and may determine any one or any combination of the pulse width, magnitude, frequency, phase, and waveform of the electrical signal applied to cell cluster 410 based on the determined target generation rate. The following will refer to... Figure 6 and Figure 7 Further, non-limiting examples of parameters of the electrical signals determined and controlled by the cell controller 420 are described. Based on the target generation rate of organoids in the cell cluster 410, the electrodes STIM_WE and STIM_CE of the stimulation channel 422 can induce the secretion of active ingredients by providing the electrical signals determined by the cell controller 420 to the cell cluster 410.

[0084] Cell reservoir 419 may be formed of a material through which target molecule 451 and active ingredient 452 pass, and may be implemented as a structure to accommodate cell clusters 410. For example, cell reservoir 419 may include a porous membrane 490 surrounding and accommodating cell clusters 410. Porous membrane 490 may be configured such that target molecule 451 and active ingredient 452 pass through porous membrane 490. Porous membrane 490 may include multiple layers. For example, porous membrane 490 may include a first membrane layer 491, a second membrane layer 492, and a supporting fiber layer 493. Porous membrane 490 may surround the entire outer edge of cell reservoir 419; however, examples are not limited thereto. For example, porous membrane 490 may cover a portion of the outer edge of cell reservoir 419, and a nonporous cover may cover the remaining portion of the outer edge of cell reservoir 419.

[0085] The first membrane layer 491 prevents immune cells in vivo (e.g., immune cells outside the cell reservoir 419) from permeating into the cell reservoir 419. The first membrane layer 491 may be formed of polytetrafluoroethylene (PTFE) and may have a thickness of about 30 micrometers (μm) and pores with a diameter of less than 0.5 μm. The second membrane layer 492 may be formed of PTFE and may have a thickness of about 15 μm and pores with a diameter of about 5 μm. The supporting fiber layer 493 may be a layer that prevents internal components (e.g., cell clusters or cell controllers) from being damaged by physical external forces (such as pressure generated in vivo) by supporting mechanical and physical structures. The supporting fiber layer 493 may be formed of polyester and may have a thickness of more than 150 μm and pores with a diameter of more than 100 μm. The thickness of each layer is not limited to those described above and may vary depending on the design. The first membrane layer 491 may be disposed adjacent to the cell clusters in the cell reservoir, and the supporting fiber layer 493 may be disposed outside the cell reservoir 419 or as an outer wall of the cell reservoir 419. The second membrane layer 492 may be disposed between the first membrane layer 491 and the supporting fiber layer 493. Due to the structure of the porous membrane 490 described above, the active ingredient 452 and the target molecule 451 can freely enter and exit the cell reservoir 419, and immune cells can be prevented from entering the cell reservoir 419. For example, the diameter of each of the active ingredient 452 and the target molecule 451 may be smaller than the diameter of the pores in each of the layers 491, 492, and 493, and the diameter of the immune cells may be larger than the diameter of the pores in one or more of the layers 491, 492, and 493.

[0086] As described above, the active ingredient 452 secreted by the organoids in the cell cluster 410 can be discharged from the cell reservoir 419, thereby being injected into the body. The injected active ingredient 452 can act on the body, thus modulating the metabolic state and altering the concentration of the target molecule 451. Whenever the secretion of the active ingredient is promoted by the cell controller 420 and / or the body's metabolic state is altered at fixed intervals through metabolism, the bioelectric pharmaceutical device can re-identify the altered metabolic state of the body.

[0087] For example, when cell cluster 410 secretes active ingredient 452 at an altered rate of active ingredient production in response to electrical stimulation, an electrochemical sensor can sense the altered concentration of target molecule 451. Therefore, a bioelectric pharmaceutical device can apply an electrical stimulation signal to cell cluster 410 and monitor feedback based on the results obtained through the secretion of active ingredient 452 by organoids within cell cluster 410. Cell controller 420 can re-identify the metabolic state based on the altered concentration and can re-determine whether to apply electrical stimulation to cell cluster 410 based on the re-identified metabolic state. Thus, whenever the secretion of the active ingredient is promoted or inhibited, cell controller 420 can measure the concentration of target molecule 451 in the body and determine whether treatment is needed (e.g., whether to re-secrete the active ingredient).

[0088] Figures 5A to 5C An example of an electrochemical sensor in a bioelectric pharmaceutical device is shown. Figures 5A to 5C In the reference numeral "E", the potential can be represented.

[0089] Bioelectric pharmaceutical devices may include electrochemical sensors configured to sense target molecules. Figures 5A to 5C The structures of electrochemical sensors 510, 520, and 530 are shown respectively. For example, the electrochemical sensors can sense electrical signals generated by the reaction between a target molecule and an enzyme. An enzyme can be applied to a sensing electrode EC_WE in the sensing channel, and the electrochemical sensor can sense electrical signals (e.g., voltage and / or current) generated due to the chemical reaction between the enzyme and the target molecule via the sensing electrode EC_WE. For example, the potential voltage of a portion of the sensing electrode EC_WE to which the enzyme is applied can change proportionally to blood glucose concentration, and a bioelectric pharmaceutical device can sense blood glucose concentration in the body based on the potential voltage.

[0090] Figure 5A The electrochemical sensor 510 can use potentiometry to measure potential voltage. For example, the electrochemical sensor 510 can measure the potential voltage V between the sensing working electrode EC_WE and the sensing reference electrode EC_RE without driving power. sens Sensing is performed. The electrochemical sensor 510 can be implemented using a molecularly imprinted polymer.

[0091] Figure 5B The electrochemical sensor 520 can use amperometry to measure current. For example, the electrochemical sensor 520 can sense the current I flowing from the sensing working electrode EC_WE to the sensing counter electrode EC_CE without driving power. sensThe electrochemical sensor 520 can be implemented using glucose oxidase (GOx).

[0092] Figure 5C The electrochemical sensor 530 can be operated using cyclic voltammetry (CV) or electrochemical impedance spectroscopy (EIS). For example, the potential voltage V between the sensing working electrode EC_WE and the sensing reference electrode EC_RE can be measured. ctrl This can be provided as driving power in the electrochemical sensor 530, and the electrochemical sensor 530 can sense the current I flowing from the sensing working electrode EC_WE to the sensing counter electrode EC_CE. sens The electrochemical sensor 530 can be implemented using boric acid.

[0093] Figure 6 and Figure 7 An example of electrical stimulation applied to a cell cluster via a bioelectric pharmaceutical device is shown.

[0094] Figure 6 The parameters of the electrical signals used to stimulate cell clusters are shown.

[0095] The cell controller can control the pulse width, current intensity, pulse frequency, phase, and waveform. The cell controller can determine and control the parameters of a single pulse 610, a pulse sequence 620 as a group of pulses, and a sequence group 630 as a group of pulse sequences 620.

[0096] The pulse width is the width of the conduction period within a single pulse 610. The conduction period is the time during which a positive or negative electrical signal is present. A positive or negative electrical signal indicates the sign of the signal applied to the working electrode. The phase width, pulse interval, sequence interval, and group interval correspond to the cutoff period, and the cutoff period is the time during which no electrical signal is present. Although for ease of description, as... Figure 6 As shown, sequence group 630 includes a single pulse sequence 620, and pulse sequence 620 includes a single pulse, but the example is not limited to this. The number of pulses in each pulse sequence 620, the number of pulse sequences 620 in each sequence group 630, and the number of groups can be changed according to settings and user control.

[0097] When an electrical signal is applied for a relatively short period of time, the cell controller can apply a monophasic pulse to the cell cluster. The monophasic pulse can be a pulse with either a positive or negative electrical signal, rather than a pulse with both positive and negative electrical signals.

[0098] like Figure 6As shown, the cell controller can apply symmetrical biphasic pulses to cell clusters. A biphasic pulse can be a pulse with alternating positive and negative electrical signals. Biphasic pulses maintain charge balance within the cell clusters and therefore can be used for longer periods compared to monophasic pulses. A symmetrical biphasic pulse can be a pulse where the intensity and width of the positive pulse are the same as, respectively, the intensity and width of the negative pulse. However, the example is not limited to this. Figure 6 In this case, asymmetric biphasic pulses can be applied to cell clusters. The asymmetric biphasic pulse can be one or both of the positive pulses having different intensities and pulse widths than the negative pulses. A single pulse 610 can have a current intensity of 0 mA to 8 mA, a pulse width of 5 μs to 2000 μs, and a frequency of 0.1 Hz to 40000 Hz.

[0099] Figure 7 The pulse frequency band that can be controlled by the cell controller is shown.

[0100] Cellular controllers can adjust the frequency of electrical stimulation based on a spectrum of biological signals. For example... Figure 7 As shown, the frequency bands controllable by the cell controller can be divided into a delta band 710 (0.1 Hz to 4 Hz), a theta band 720 (4 Hz to 8 Hz), an alpha band 730 (8 Hz to 13 Hz), a beta band 740 (13 Hz to 30 Hz), a slow gamma band 750 (30 Hz to 70 Hz), a fast gamma band 760 (70 Hz to 150 Hz), a slow oscillation band 770 (200 Hz to 300 Hz), a fast oscillation band 780 (300 Hz to 400 Hz), and a peak band 790 exceeding 400 Hz.

[0101] The cell controller can use an electrical signal with a pulse having a frequency of one or more of the frequency bands 710 to 790 described above to promote the secretion of active ingredients by organoids in the cell cluster. For example, the cell controller determines the frequency of the electrical signal applied to the cell cluster to be within one of the β frequency band 740, the slow γ frequency band 750 including 40 Hz, the fast γ frequency band 760, and the peak frequency band 790 exceeding 400 Hz.

[0102] For example, the β-organoids of the cell cluster may include adrenergic receptors, and these receptors may respond to both the α-band 730 and the β-band 740. In one example, the cell controller may inhibit the secretion of an active ingredient (e.g., insulin) by applying an electrical signal with a frequency of the α-band 730. In another example, the cell controller may promote insulin secretion by applying an electrical signal with a frequency of the β-band 740. However, the examples are not limited to these; the cell controller may also promote insulin secretion by applying an electrical signal with a frequency of approximately 40 Hz to the cell cluster that includes β-cell organoids.

[0103] Furthermore, the cell controller can promote the secretion of active ingredients by organoids within the cell cluster by applying an electrical signal with a peak frequency of 790 Å to the cell cluster. For example, the cell controller can apply an electrical signal with a peak frequency of 790 Å to activate the cell ion gate of the organoids within the cell cluster. Additionally, the cell controller can adjust the pulse width of the electrical stimulation to activate the cell ion gate of the organoids within the cell cluster.

[0104] However, the frequency band of the cell controller is not limited to those described above. For example, to promote the secretion of active ingredients by organoids in a cell cluster, the cell controller can apply stimulation pulses with any other frequency band.

[0105] Figure 8 An example of an electrode channel in a bioelectric pharmaceutical device is shown.

[0106] Reference Figure 8 The cell controller 820 may include a channel switch 821, a stimulator 822, a processor 823 (e.g., one or more processors), an electrochemical sensor 824, a power manager 825, a battery 826, an energy harvester 827, and a communicator 828. The stimulator 822, electrochemical sensor 824, power manager 825, battery 826, energy harvester 827, and communicator 828 may communicate with... Figure 2 The similar operations described above will not be repeated here.

[0107] In addition to the control channels described above for promoting and inhibiting the secretion of active ingredients by organoids in cell cluster 810, the bioelectric pharmaceutical device may also include additional electrode channels. For example, the control channel may be a channel between cell cluster 810 and cell controller 820, and the body channel may be a channel between body 890 and cell controller 820. The active ingredient channel may be a channel between cell cluster 810 and body 890. The bioelectric pharmaceutical device may include control channel electrodes, body channel electrodes, and active ingredient channel electrodes for each channel.

[0108] The control channel electrode may be an electrode configured to allow the application of electrical signals to the cell cluster 810, and may include stimulation channel electrodes and sensing channel electrodes as described above (e.g., as referred to above). Figure 2 The electrodes for the stimulation channel and the electrodes for the sensing channel are described.

[0109] The active ingredient channel electrode may be an electrode disposed between the cell cluster 810 and the body 890 (e.g., blood vessel) and may be associated with the implantation of a bioelectric pharmaceutical device and the absorption of active ingredients secreted by organoids in the cell cluster 810.

[0110] Body channel electrodes can be electrodes configured to allow the application of electrical signals to the body 890 (e.g., blood vessels) and can be associated with the implantation of bioelectric pharmaceutical devices.

[0111] Figure 9 An example of an implantation procedure performed by a bioelectric pharmaceutical device is shown.

[0112] The bioelectric pharmaceutical device can perform an implantation procedure to insert the device into the body. After a predetermined time, it can be determined that the bioelectric pharmaceutical device is completely implanted. A cell controller 920 can perform sensing and stimulation operations to improve the implantation rate of the bioelectric pharmaceutical device in the in vivo environment via active ingredient channels and body channels. The cell controller 920 can enhance the acceptability of the active ingredient through electrical stimulation, which induces treatment in the area surrounding the body site where the bioelectric pharmaceutical device is inserted (e.g., blood vessels or capillaries) via active ingredient channels and body channels. By applying electrical stimulation to capillaries 992 via active ingredient channels and body channels, the regeneration of capillaries 992 can be promoted to enhance the acceptability of the active ingredient.

[0113] For example, in response to the bioelectric pharmaceutical device being in implantation mode, the cell controller 920 can promote the regeneration of capillaries 992 adjacent to the bioelectric pharmaceutical device via active ingredient channel electrodes and body channel electrodes. For instance, the cell controller 920 can apply electrical stimulation to blood vessels 991 and capillaries 992 external to the bioelectric pharmaceutical device by applying an electrical signal from the active ingredient working electrode DC_WE of the active ingredient channel 923 to the active ingredient counter electrode DC_CE of the active ingredient channel 923. Furthermore, the cell controller 920 can apply electrical stimulation to blood vessels 991 and capillaries 992 by applying an electrical signal from the body working electrode BC_WE of the body channel 924 to the body counter electrode BC_CE of the body channel 924. The cell controller 920 can promote the deposition of extracellular matrix (ECM) through electrical stimulation of the active ingredient channel 923 to increase epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF). Therefore, in response to electrical stimulation, healing and regeneration of capillaries 992 can occur. As described above, capillaries 992 can regenerate in response to electrical stimulation. Therefore, capillaries 992 can grow closer to the bioelectric pharmaceutical device, reducing the gap between the capillaries 992 and the site from which the active ingredient is discharged from the bioelectric pharmaceutical device (e.g., the outer surface of the porous membrane). Consequently, in response to the reduced gap, the connection between the capillaries 992 and the bioelectric pharmaceutical device can be strengthened. Therefore, in response to the strengthened connection, the implantation rate of the bioelectric pharmaceutical device can be further improved.

[0114] To promote the regeneration of capillaries 992 in the implantation mode described above, the cell controller 920 can apply direct current (DC) stimulation or low-frequency alternating current (AC) stimulation as iontophoretic stimulation. For example, the frequency of the low-frequency AC stimulation can include... Figure 7 In the δ band 710 or θ band 720.

[0115] Figure 10 An example of a therapeutic procedure performed by a bioelectric pharmaceutical device is shown.

[0116] The treatment mode indicates the stage at which the bioelectric pharmaceutical device secretes an active ingredient for treatment. The cell controller 1020 monitors the concentration of the target molecule in the body via control channels and body channels. The cell controller 1020 can provide electrical stimulation to activate organoids in the cell cluster 1010 to secrete the active ingredient, or terminate electrical stimulation, via control channels. The bioelectric pharmaceutical device can enhance therapeutic efficacy by regulating the rate of active ingredient production based on sensed information.

[0117] In response to the bioelectric pharmaceutical device being in therapeutic mode, the cell controller 1020 can promote the secretion of active ingredients from organoids within the cell cluster 1010 by applying electrical signals to the cell cluster 1010 via electrodes through a control channel. For example, the cell controller 1020 can apply electrical signals at a predetermined frequency (e.g., Figure 7 An electrical signal (at any of frequencies 710 to 790 shown) is applied from the stimulation working electrode STIM_WE of stimulation channel 1021 to the stimulation counter electrode STIM_CE of stimulation channel 1021 to apply electrical stimulation to cell cluster 1010. Organoids in the electrically stimulated cell cluster 1010 may secrete an active ingredient 1052. The active ingredient 1052 secreted by the organoids in cell cluster 1010 may be discharged from the cell reservoir, and the discharged active ingredient 1052 may be absorbed into capillaries 1092.

[0118] As described above, the cell controller 1020 can monitor the concentration of target molecules introduced into the cell reservoir via sensing channel electrodes and body channel electrodes, as well as the concentration of target molecules in the body, and can provide electrical stimulation based on the monitoring results to activate organoid secretion of active ingredients in the cell cluster 1010. Therefore, the bioelectric pharmaceutical device can enhance the secretion capacity of organoid active ingredients 1052 in the cell cluster 1010 through electrical stimulation to improve therapeutic efficacy. When the capillaries 1092 are as described above... Figure 9 When the plant grows closer to the bioelectric pharmaceutical device, the active ingredient 1052 secreted by the bioelectric pharmaceutical device can be more effectively absorbed into the human body.

[0119] Figure 11 An example is shown of promoting the absorption of active ingredients through a bioelectric pharmaceutical device.

[0120] The cell controller 1120 can control the diffusion rate and direction of the ionized active ingredient 1154 by applying an electrical signal to the outside via the active ingredient channel electrode in therapeutic mode. In other words, in response to the bioelectric pharmaceutical device being in therapeutic mode, the cell controller 1120 can induce the active ingredient, which has been discharged from the bioelectric pharmaceutical device and bound to an ion transporter, to move into the bloodstream by applying an electrical signal via the active ingredient channel electrode.

[0121] For example, such as Figure 11 As shown, active ingredient 1152 discharged from the bioelectric pharmaceutical device through a porous membrane can bind to and be ionized by an ion transporter 1155 adjacent to the bioelectric pharmaceutical device. The active ingredient bound to the ion transporter 1155 may be referred to as ionized active ingredient 1154. Ion transporter 1155 may include, for example, calcium (Ca) present in the body. 2+ ) ions or sodium (Na) +Sodium ions. Sodium can bind with blood glucose, and calcium can bind with insulin.

[0122] exist Figure 11 In this embodiment, the cell controller 1120 can independently apply an electrical signal through the active ingredient channel 1123, independent of the operation of promoting organoid secretion of active ingredients in cell clusters via stimulation channels. The cell controller 1120 can form an electrical path from the electrodes of the bioelectric pharmaceutical device via capillaries by applying an electrical signal from the active ingredient working electrode DC_WE to the active ingredient counter electrode DC_CE. The polar ionized active ingredient 1154 can be accelerated along the electrical path; therefore, the cell controller 1120 can form an electrical path through the active ingredient channel 1123 to control the diffusion direction of the ionized active ingredient 1154. Furthermore, the cell controller 1120 can change the magnitude of the electrical signal applied to the active ingredient channel 1123 to control the diffusion rate of the ionized active ingredient 1154. For example, the cell controller 1120 can increase the magnitude of the electrical signal applied to the active ingredient channel 1123 to increase the diffusion rate of the ionized active ingredient 1154, or the cell controller 1120 can decrease the magnitude to decrease the diffusion rate. For example, the cell controller 1120 can apply a DC electrical signal or a low-frequency AC electrical signal to the active ingredient channel 1123 as an iontophoresis stimulus.

[0123] Therefore, bioelectric pharmaceutical devices can use microcurrents as additional electrical stimulation to secrete and deliver ionized active ingredient 1154 bound to ion transporters, thereby increasing the rate at which active ingredient 1152 is introduced into the bloodstream.

[0124] Figure 12 An example of the overall structure of the bioelectric pharmaceutical device 1200 is shown.

[0125] Figure 12 The bioelectric pharmaceutical device 1200 can be used with reference to the above. Figures 1 to 11 It can operate on any or all of the various channels described, and can deliver the active ingredients to the body 1290.

[0126] The bioelectric pharmaceutical device 1200 can be implemented as a system in which a cell cluster 1210 and a cell controller 1220 are integrated. For example, a porous membrane can accommodate both the cell reservoir including the cell cluster 1210 and the cell controller 1220. However, the examples are not limited to this, and the bioelectric pharmaceutical device 1200 can be implemented with the following structure: the cell reservoir including the cell cluster 1210 is disposed inside the porous membrane, the cell controller 1220 is separately encapsulated outside the porous membrane, and the cell reservoir is separable from the cell controller 1220.

[0127] In the following text, reference will be made to Figure 13An example describing the structure of a porous membrane that integrally accommodates cell clusters 1210 and cell controllers 1220 is provided, and references will be made to... Figure 14 and Figure 15 An example describing a structure in which the cell reservoir can be separated from the cell controller 1220.

[0128] Figure 13 An example of the application of a bioelectric pharmaceutical device is shown.

[0129] Figure 13 The bioelectric pharmaceutical device is a device that integrates a cell cluster 1310 and a cell controller 1320. For example, a porous membrane 1330 may accommodate the cell controller 1320 and a cell reservoir that accommodates the cell cluster 1310 (e.g., as described above). Figure 4 The above).

[0130] In response to a sensed concentration level of the target molecule within a first range, cell controller 1320 may apply electrical stimulation to cell cluster 1310 to promote the secretion of an active ingredient by organoids in cell cluster 1310. In response to a sensed concentration level of the target molecule within a second range, cell controller 1320 may interrupt (e.g., stop or reduce) the electrical stimulation of cell cluster 1310. The first and second ranges are different from each other. In one example, when the concentration level of the target molecule is determined to be within the first range, the bioelectric pharmaceutical device may regulate the concentration level of the target molecule to be within the second range by promoting the secretion of an active ingredient by organoids in cell cluster 1310. In another example, when the first range is greater than the second range, the bioelectric pharmaceutical device may use the active ingredient secreted by organoids in cell cluster 1310 to reduce the concentration level of the target molecule from the first range to the second range. However, the examples are not limited to these. In another example, when the first range is less than the second range, the bioelectric pharmaceutical device may use the active ingredient secreted by organoids in cell cluster 1310 to increase the concentration level of the target molecule from the first range to the second range. The first range can be an abnormal range, and the second range can be a normal range.

[0131] like Figure 13 As shown, the bioelectric pharmaceutical device can sense blood glucose 1311 as a target molecule, and organoids including β-cell organoids in the cell cluster 1310 can secrete insulin 1312 as an active ingredient targeting blood glucose 1311.

[0132] In addition to the cell cluster 1310 and cell controller 1320 described above, the porous membrane 1330 may also accommodate electrodes for control channels (e.g., stimulation channels 1321 and sensing channels 1322). The porous membrane 1330 may have structures that allow glucose 1311 and oxygen to be introduced into the cell reservoir and allow insulin 1312 to be expelled, and surrounds the cell cluster 1310, the cell controller 1320, and the electrodes for the control channels. Figure 13 As shown, cell cluster 1310 can be a 3D structure, for example, β-cell organoids fused therein with a hydrogel. An electrochemical sensor formed in the electrode of sensing channel 1322 can sense blood glucose levels in the body.

[0133] In response to a sensed blood glucose level exceeding a threshold, the cell controller 1320 can apply electrical stimulation to the cell cluster 1310 to promote insulin secretion from organoids within the cell cluster 1310. Therefore, a bioelectric pharmaceutical device can use the cell cluster 1310, comprising a fusion of stem cells capable of secreting insulin 1312 for the treatment of diabetes, to maintain blood glucose levels within a normal range.

[0134] Bioelectric pharmaceutical devices can have, for example Figure 13 The structure shown integrates an electrochemical sensor, cell cluster 1310, and cell controller 1320; however, the example is not limited thereto. See below for further details. Figure 14 An example describing a structure in which cell clusters and cell controller 1420 can be separated.

[0135] Figure 14 and Figure 15 An example of the structure of a cell delivery system that can be separated from a bioelectric pharmaceutical device is shown.

[0136] Figure 14 The structure of the cell delivery system is shown to be separable from the bioelectric pharmaceutical device 1400.

[0137] The bioelectric pharmaceutical device 1400 may include a cell controller 1420 and a cell reservoir 1430 configured to be separable from the cell controller 1420.

[0138] Cell controller 1420 may include stimulator 1422, processor 1423 (one or more processors), electrochemical sensor 1424, power manager 1425, battery 1426, and energy harvester 1427 (e.g., similar to...). Figure 2 and Figure 8As described above, the cell controller 1420 may also include an antenna 1428. The cell controller 1420 may be hermetically packaged, and each element of the cell controller 1420 may be protected from ingress of foreign substances and liquids by the hermetically packaged enclosure. The antenna 1428 may be exposed outside the hermetically packaged enclosure and may be configured to communicate via a communicator (e.g., Figure 2 The communicator 228 and Figure 8 The cell controller 1420 may establish wireless communication with an external device (one of the communicators 828) or wirelessly receive signals from an external device. Furthermore, the cell controller 1420 may include a feedthrough connector 1429 corresponding to the control channel, serving as a connector for establishing an electrical connection with the cell reservoir 1430.

[0139] Cell reservoir 1430 can accommodate cell clusters and is separable from cell controller 1420. Cell reservoir 1430 may include electrodes that can apply electrical signals to active ingredient channels in the body. Cell reservoir 1430 can be electrically connected to cell controller 1420, and based on the control of cell controller 1420, electrical signals can be applied to the electrodes of the active ingredient channels. Cell controller 1420 can apply electrical signals to the body through body channels. Cell controller 1420 and cell reservoir 1430 can be electrically connected via an interface through a control channel. The outer edge of cell reservoir 1430 can be encapsulated by a porous membrane 1419.

[0140] The cell-accommodating space 1410 can be the internal space of the cell reservoir 1430, and can accommodate a cell core 1411 and a coating 1412 for the cell core 1411. For example, the cell core 1411 can be a β-pancreatic cell organoid, and the coating 1412 can be a hydrogel as a biomaterial. The cell-accommodating space 1410 can accommodate at least one cell cluster fused with the cell core 1411 and the coating 1412.

[0141] The cell reservoir 1430 may include electrodes corresponding to control channels and active ingredient channels, as well as a cell containment space 1410. A stimulation working electrode STIM_WE and a stimulation counter electrode STIM_CE for electrostimulation may be disposed within a porous membrane 1419 of the cell reservoir 1430. Furthermore, a sensing working electrode EC_WE, a sensing reference electrode EC_RE, and a sensing counter electrode EC_CE for an electrochemical sensor may be disposed within the porous membrane 1419. The electrodes corresponding to the control channels in the cell reservoir 1430 may be as described above. Figure 14 As described, however, the examples are not limited to this. Electrodes corresponding to the active ingredient channels may additionally be disposed outside the cell reservoir 1430.

[0142] In addition, the cell reservoir 1430 may also include an enzyme reservoir 1440. The enzyme reservoir 1440 may store an enzyme that generates an electrical signal through a chemical reaction with a target molecule. For example, when the target molecule is blood glucose, the enzyme reservoir 1440 may store glucose oxidase (GOx). The enzyme reservoir 1440 may be positioned adjacent to an electrode of the sensing channel (e.g., the sensing working electrode EC_WE).

[0143] Cell storage device 1430 can be configured to be replaceable. When cell clusters are depleted, the user can replace cell storage device 1430 with a new cell storage device.

[0144] Cell storage 1430 can be configured to re-inject cell clusters. The cell clusters may include the fusion of organoids and biomaterials as described above, and the organoids may be protected by the biomaterials during injection. Therefore, cell clusters can be injected through loading port 1431. When the cell clusters stored in cell storage 1430 are depleted, the user can replenish cell storage 1430 with new cell clusters. For example, the cell storage 1430 and enzyme storage 1440 described above can be configured to re-inject through loading ports 1431 and 1432. Cell storage 1430 may include loading port 1431 through which additional cell clusters are injected externally. Cell storage 1430 may include loading port 1432 through which additional enzymes are injected externally.

[0145] Reference Figure 15 The cell reservoir 1530, detachable from the bioelectric pharmaceutical device, can be configured as a pod. The bioelectric pharmaceutical device can be inserted into a subcutaneous body site (e.g., the dermis 1591). For example, the dermis 1591 is a subcutaneous layer with a thickness of up to approximately 5 mm. The bioelectric pharmaceutical device can be injected between the subcutaneous layer 1592 and the skin.

[0146] The cell controller 1520 may include a flow path through which a body fluid flow 1599 passes. Furthermore, the cell controller 1520 may house a cell reservoir 1530 within the flow path, and the body fluid flow 1599 flowing into the cell controller 1520 may be discharged from the cell controller 1520 via the cell reservoir 1530 through the flow path. For example, the cell controller 1520 may allow body fluid to flow therethrough an inlet formed at its front end, and may discharge body fluid through an opening 1529 formed at its distal end.

[0147] Furthermore, the cell reservoir 1530 may include a housing that can be inserted into the cell controller 1520 and is replaceable through the opening 1529. In one example, the cell reservoir 1530, mounted in the cell controller 1520, is movable longitudinally along the cell controller 1520 and can be pulled out through the opening 1529 to detach from the cell controller 1520. In another example, the cell reservoir 1530 can be inserted through the opening 1529, is movable longitudinally along the cell controller 1520, and is compatible with the cell controller 1520.

[0148] The cell reservoir 1530 may house cell clusters and an electrochemical sensor 1524, and may include electrodes disposed externally to the cell reservoir 1530 for electrical connection to a cell controller 1520. For example, when the cell controller 1520 and the cell reservoir 1530 are combined, the electrode connector 1521 of the control channel of the cell controller 1520 may be configured to electrically connect to the stimulation channel electrode 1531 and the sensing channel electrode 1532 of the cell reservoir 1530. Figure 15 As shown, the body channel electrode and the active ingredient channel electrode are disposed outside the cell controller 1520; however, the example is not limited to this.

[0149] An electrochemical sensor 1524 may be formed in a cell reservoir 1530. For example, the cell reservoir 1530 may include an inlet 1538 through which liquid flows into the cell reservoir 1530, an outlet 1539 through which liquid flows out, and a flow path formed between the inlet 1538 and the outlet 1539. A porous membrane may be disposed in the inlet 1538 and the outlet 1539. The flow path may be defined by an inner surface 1504 of the cell reservoir 1530. An enzyme capable of reacting with a target molecule (e.g., blood glucose) may be applied to the inner surface 1504 of the cell reservoir 1530. The applied enzyme may be electrically connected to a sensing electrode exposed outside the cell reservoir 1530. Thus, a target molecule introduced into the cell reservoir 1530 through the flow path may react with the enzyme.

[0150] Furthermore, the cell reservoir 1530 may contain cell clusters within a portion of the flow path (e.g., cell containment space 1510). Stimulation channel electrodes 1531, exposed outside the cell reservoir 1530, may be connected to the cell containment space 1510 within the cell reservoir 1530. Organoids within the cell clusters may secrete active ingredients based on electrical stimulation determined by the processor 1522 (e.g., one or more processors) of the cell controller 1520. The active ingredients secreted by the organoids within the cell clusters may be discharged through outlet 1539.

[0151] Despite Figure 15As shown, the cell storage device 1530 is in the form of a cylinder, but this is just an example, and the shapes of the cell storage device 1530 and the cell controller 1520 are not limited to this.

[0152] Figure 16 An example of a method for secreting active ingredients using a bioelectric pharmaceutical device is shown.

[0153] A method for controlling a bioelectric pharmaceutical device inserted into the body is described. For example, the bioelectric pharmaceutical device may include an electrochemical sensor, a cell reservoir, and a cell controller.

[0154] Reference Figure 16 In operation 1610, an electrochemical sensor can sense target molecules in the body. For example, a bioelectric pharmaceutical device can electrochemically sense blood glucose concentration in the body.

[0155] In operation 1620, the bioelectric pharmaceutical device can apply an electrical signal to a cell cluster that induces the secretion of an active ingredient, based on the results obtained by sensing the target molecule. In the cell cluster, organoids capable of secreting the active ingredient are embedded in the biomaterial.

[0156] According to examples, bioelectric pharmaceutical devices can improve implantation rates by applying electrical stimulation based on cellular state and can enhance the secretion capacity of active ingredients (e.g., insulin secretion capacity). Furthermore, bioelectric pharmaceutical devices can exhibit high glucose detection capabilities using electrochemical sensors. Therefore, bioelectric pharmaceutical devices can accurately secrete and deliver the required amount of active ingredients based on the body's state.

[0157] However, Figure 16 The method of secreting active ingredients is not limited to this, and can be compared with the above-mentioned methods. Figures 1 to 15 At least one of the described operations is executed in parallel or sequentially.

[0158] In this regard Figures 1 to 16The described bioelectric pharmaceutical devices include: cell controllers, channel switches, stimulators, processors, electrochemical sensors, power managers, batteries, energy harvesters, communicators, controllers, cell controllers, stimulation channels, sensing channels, active ingredient channels, body channels, antennas, feedthrough connectors, electrodes, bioelectric pharmaceutical device 100, cell controller 120, bioelectric pharmaceutical device 200, cell controller 220, channel switch 221, stimulator 222, processor 223, electrochemical sensor 224, power manager 225, battery 226, energy harvester 227, communicator 228, controller 320, cell controller 420, stimulation channel 422, sensing channel 421, electrochemical sensors 510, 520 and 530, cell controller 820, channel switch 821, stimulator 822, processor 823, electrochemical sensor 824, and power manager 820. 5. Battery 826, Energy harvester 827, Communicator 828, Cell controller 920, Active ingredient channel 923, Body channel 924, Cell controller 1020, Stimulation channel 1021, Cell controller 1120, Active ingredient channel 1123, Bioelectric pharmaceutical device 1200, Cell controller 1220, Cell controller 1320, Stimulation channel 1321, Sensing channel 1322, Bioelectric pharmaceutical device 1400, Cell controller 1420, Stimulator 1422, Processor 1423, Electrochemical sensor 1424, Power manager 1425, Battery 1426, Energy harvester 1427, Antenna 1428, Feedthrough connector 1429, Cell controller 1520, Electrochemical sensor 1524, Stimulation channel electrode 1531, Sensing channel electrode 1532, Devices, units, modules, apparatuses and other components are implemented by hardware components. Examples of hardware components that can be used to perform the operations described in this application include, where appropriate, controllers, sensors, generators, drivers, memories, comparators, arithmetic logic units, adders, subtractors, multipliers, dividers, integrators, and any other electronic components configured to perform the operations described in this application. In other examples, one or more of the hardware components performing the operations described in this application are implemented by computing hardware (e.g., by one or more processors or computers). The processor or computer may be implemented by one or more processing elements, such as arrays of logic gates, controllers and arithmetic logic units, digital signal processors, microcomputers, programmable logic controllers, field-programmable gate arrays, programmable logic arrays, microprocessors, or any other means or combination of means configured to respond to and execute instructions in a defined manner to achieve a desired result. In one example, the processor or computer includes or is connected to one or more memories storing instructions or software executed by the processor or computer.Hardware components implemented by a processor or computer can execute instructions or software (such as an operating system (OS) and one or more software applications running on the OS) for performing the operations described in this application. The hardware components can also access, manipulate, process, create, and store data in response to the execution of instructions or software. For simplicity, the singular terms "processor" or "computer" are used in the description of the examples described in this application; however, in other examples, multiple processors or computers may be used, or a processor or computer may include multiple processing elements, or multiple types of processing elements, or both. For example, a single hardware component, or two or more hardware components, may be implemented by a single processor, or two or more processors, or a processor and a controller. One or more hardware components may be implemented by one or more processors, or a processor and a controller, and one or more other hardware components may be implemented by one or more other processors, or additional processors and additional controllers. One or more processors, or a processor and a controller, may implement a single hardware component, or two or more hardware components. The hardware components can have any one or more different processing configurations, examples of which include: a single processor, a discrete processor, a parallel processor, a single instruction single data (SISD) multiprocessing, a single instruction multiple data (SIMD) multiprocessing, multiple instruction single data (MISD) multiprocessing, and multiple instruction multiple data (MIMD) multiprocessing.

[0159] Figures 1 to 16 The methods for performing the operations described in this application, as shown, are executed by computing hardware (e.g., one or more processors or a computer), which is implemented as described above to execute instructions or software to perform the operations performed by the methods described in this application. For example, a single operation, or two or more operations, may be executed by a single processor, or two or more processors, or a processor and a controller. One or more operations may be executed by one or more processors, or a processor and a controller, and one or more other operations may be executed by one or more other processors, or additional processors and additional controllers. One or more processors, or a processor and a controller, may execute a single operation, or two or more operations.

[0160] Instructions or software for controlling computing hardware (e.g., one or more processors or computers) to implement hardware components and perform the methods described above can be written as computer programs, code segments, instructions, or any combination thereof, for individually or collectively instructing or configuring one or more processors or computers to operate as machines or special-purpose computers to perform operations performed by the hardware components and methods described above. In one example, the instructions or software include machine code (such as machine code generated by a compiler) that is directly executed by one or more processors or computers. In another example, the instructions or software include high-level code that is executed by one or more processors or computers using an interpreter. The instructions or software can be written using any programming language based on the block diagrams and flowcharts shown in the accompanying drawings and the corresponding description used herein, which disclose algorithms for performing operations performed by the hardware components and methods described above.

[0161] Instructions or software used to control computing hardware (e.g., one or more processors or computers) to implement hardware components and perform the methods described above, as well as any associated data, data files, and data structures, may be recorded, stored, or fixed in, or on, one or more non-transitory computer-readable storage media. Examples of non-transitory computer-readable storage media include: read-only memory (ROM), programmable random access read-only memory (PROM), electrically erasable programmable read-only memory (EEPROM), random access memory (RAM), dynamic random access memory (DRAM), static random access memory (SRAM), flash memory, non-volatile memory, CD-ROM, CD-R, CD+R, CD-RW, CD+RW, DVD-ROM, DVD-R, DVD+R, DVD-RW, DVD+RW, DVD-RAM, BD-ROM, BD-R, BD-R LTH, BD-RE, Blu-ray or optical disc storage, hard disk drive (HDD), solid-state drive (SSD), card storage (such as multimedia cards or microcards (e.g., Secure Digital (SD) or Extreme Digital (XD))), magnetic tape, floppy disk, magneto-optical data storage device, optical data storage device, hard disk, solid-state drive, and any other device configured to store instructions or software and any associated data, data files, and data structures in a non-transitory manner, and to provide instructions or software and any associated data, data files, and data structures to one or more processors or computers, enabling one or more processors or computers to execute the instructions. In one example, the instructions or software and any associated data, data files, and data structures are distributed across a networked computer system, such that the instructions and software and any associated data, data files, and data structures are stored, accessed, and executed in a distributed manner by one or more processors or computers.

[0162] While this disclosure includes specific examples, it will be clear upon understanding this disclosure that various changes in form and detail may be made to these examples without departing from the spirit and scope of the claims and their equivalents. The examples described herein are to be considered descriptive only and not for limiting purposes. The description of features or aspects in each example is to be considered applicable to similar features or aspects in other examples. Suitable results may be achieved if the described techniques are performed in a different order, and / or if components in the described system, architecture, apparatus, or circuit are combined in a different manner, and / or replaced or supplemented by other components or their equivalents. Therefore, the scope of the disclosure is not limited by the specific embodiments but by the claims and their equivalents, and all variations within the scope of the claims and their equivalents shall be construed as included in the disclosure.

Claims

1. A bioelectric pharmaceutical device, comprising: A cell reservoir is configured to contain cell clusters, the cell clusters including organoids fused with biomaterials, wherein the biomaterials include hydrogels; The cell controller is configured to use electrical signals to control the secretion of active ingredients by organoids in cell clusters; Electrochemical sensors are configured to sense target molecules; and Control channel electrodes are configured to apply electrical signals to cell clusters, wherein the control channel electrodes include stimulation channel electrodes and sensing channel electrodes. The stimulation channel electrode and the sensing channel electrode are connected to the cell controller and are electrically connected to the cell cluster and / or neighboring cell clusters. The stimulation channel electrode and the sensing channel electrode are located in the cell reservoir. In order to control secretion, the cell controller is configured to regulate the rate of production of organoid active ingredients in the cell cluster based on the results of sensing target molecules.

2. The bioelectric pharmaceutical device according to claim 1, wherein, The cell clusters are contained in a cell reservoir, and the cell clusters include a hydrogel and β-cell organoids disposed within the hydrogel.

3. The bioelectric pharmaceutical device according to claim 1, wherein, In order to sense the target molecule, the electrochemical sensor is configured to sense another electrical signal generated by the reaction between the target molecule and the enzyme.

4. The bioelectric pharmaceutical device according to claim 1, wherein, To control secretion, the cell controller is configured to perform one or both of the following based on the sensed concentration of the target molecule: Apply electrical stimulation that promotes the secretion of organoid active ingredients in cell clusters; and Interruption of electrical stimulation.

5. The bioelectric pharmaceutical device according to claim 4, wherein, Interrupting electrical stimulation involves either reducing the level of electrical stimulation or terminating the application of electrical stimulation, or both.

6. The bioelectric pharmaceutical device according to claim 1, wherein, To control secretion, the cell controller is configured as follows: Identify the body's metabolic state based on the concentration of the target molecules sensed; and The decision to apply electrical stimulation to cell clusters is based on the identified metabolic state.

7. The bioelectric pharmaceutical device according to claim 6, wherein, To sense the target molecule, the electrochemical sensor is configured to: sense changes in the concentration of the target molecule in response to organoids in a cell cluster secreting an active ingredient at a regulated rate of production based on electrical stimulation; and To control secretion, the cell controller is configured to: re-identify metabolic states based on the changed concentrations, and re-determine whether to apply electrical stimulation to the cell clusters based on the re-identified metabolic states.

8. The bioelectric pharmaceutical device according to claim 1, wherein, To control secretion, the cell controller is configured as follows: In response to the sensed concentration level of the target molecule within a first range, an electrical stimulus that promotes the secretion of organoid active ingredients in the cell cluster is applied to the cell cluster. and In response to the sensed concentration level of the target molecule within a second range, electrical stimulation of the cell cluster is interrupted.

9. The bioelectric pharmaceutical device according to claim 1, wherein, The electrochemical sensor is configured to sense the body's blood glucose levels, and To control secretion, the cell controller is configured to apply electrical stimulation to the cell cluster that promotes insulin secretion from organoids in the cell cluster in response to a sensed blood glucose level exceeding a threshold level.

10. The bioelectric pharmaceutical device according to claim 9, wherein, The active ingredient includes insulin, and the target molecule includes blood glucose.

11. The bioelectric pharmaceutical device according to claim 1, wherein, To control secretion, the cell controller is configured as follows: Based on the results of sensing the target molecule, the target generation rate of the active ingredient is determined. and The pulse width, size, frequency, phase, and waveform of the electrical signal are determined based on a defined target generation rate, wherein the electrical signal is applied to a cluster of cells.

12. The bioelectric pharmaceutical device according to claim 1, wherein, To control secretion, the cell controller is configured as follows: The frequency of the electrical signal is determined to be within any one of the beta band, the gamma band including 40 Hz, and the peak band exceeding 400 Hz. Electrical signals are applied to cell clusters.

13. The bioelectric pharmaceutical device according to claim 1 or 2, further comprising: Active ingredient channel electrodes are positioned between cell clusters and blood vessels; and Body channel electrodes are configured to apply another electrical signal to blood vessels.

14. The bioelectric pharmaceutical device according to claim 13, wherein, The cell controller is configured to, in response to the bioelectric pharmaceutical device being in implantation mode, use active ingredient channel electrodes and body channel electrodes to promote the regeneration of capillaries adjacent to the bioelectric pharmaceutical device.

15. The bioelectric pharmaceutical device according to claim 1 or 2, wherein, To control secretion, the cell controller is configured to: in response to the bioelectric pharmaceutical device being in therapeutic mode, apply electrical signals to the cell clusters by using control channel electrodes to promote the secretion of active ingredients by organoids in the cell clusters.

16. The bioelectric pharmaceutical device according to claim 13, wherein, The active ingredient is expelled from the outside of the bioelectric pharmaceutical device and binds to the ion transporter, and The cell controller is configured to induce the movement of an active ingredient into the bloodstream in response to the bioelectric pharmaceutical device being in a therapeutic mode by applying another electrical signal to the outside of the bioelectric pharmaceutical device using an active ingredient channel electrode.

17. The bioelectric pharmaceutical device according to claim 16, wherein, In order to apply the other electrical signal to the outside of the bioelectric pharmaceutical device, the cell controller is configured to form an electrical path between the blood vessel and the active ingredient channel electrode by applying one of a direct current stimulation and an alternating current stimulation to the active ingredient channel electrode.

18. The bioelectric pharmaceutical device according to claim 1 or 2, wherein, The cell reservoir is configured to be detachable from the cell controller.

19. The bioelectric pharmaceutical device according to claim 18, wherein, The cell storage device includes a loading port configured to receive an injection of additional cell clusters from outside the bioelectric pharmacy device.

20. The bioelectric pharmaceutical device according to claim 18, wherein, The cell reservoir is configured to house an electrochemical sensor, and the cell reservoir includes electrodes disposed externally to be electrically connected to a cell controller.

21. A non-transitory computer-readable storage medium storing instructions, said instructions, when executed by a processor, configuring the processor to perform operations, said operations including: Electrochemical sensors placed in cell reservoirs are used to sense the concentration levels of target molecules; The target production rate of the active ingredient secreted by organoids in the cell clusters set in the cell reservoir is determined based on the concentration level. The electrical signal to be applied to the organoid is determined based on the target generation rate; and Electrical signals are applied to organoids using control channel electrodes to induce the secretion of active ingredients at a target production rate. The control channel electrode includes a stimulation channel electrode and a sensing channel electrode, and the stimulation channel electrode and the sensing channel electrode are disposed in a cell reservoir containing cell clusters. The stimulation channel electrode and the sensing channel electrode are electrically connected to the cell cluster and / or neighboring cell clusters.

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