Abstract:
In one aspect, an ingestible, electrical device, comprises a substrate comprising a reservoir that is configured to hold one or more substances; a first film covering the reservoir, wherein the first film is at least partially metallic; a charge storage system connected to the first film, the charge storage system configured to deliver a transient electrochemical potential to the first film; wherein the first film is configured to prevent exposure of the substance to an aqueous environment in an organism, while the charge storage system delivers the transient electrochemical potential to the first film; and wherein the first film is configured for dissolution to expose the one or more substances to the aqueous environment in the organism, after the charge storage system stops delivering the transient electrochemical potential to the first film.

Description:
CLAIM OF PRIORITY 
     This application is a §371 National Stage Application of PCT/US2014/061910, filed Oct. 23, 2014, which, in turn, claims the benefit of priority under 35 U.S.C. §119(e) to provisional U.S. Patent Application No. 61/961,833 filed Oct. 24, 2013, the entire contents of each of which are hereby incorporated by reference. 
    
    
     FIELD OF USE 
     The present disclosure relates generally to an ingestible, electrical device, and specifically to an electrical device that delivers a substance to the gastrointestinal tract of an organism. 
     BACKGROUND 
     Oral delivery systems may control the release of substances to the gastrointestinal tract. Some systems may be designed for controlled release applications where a substance is slowly released in the gastrointestinal tract over a period of time. These systems may not be capable of encapsulating and protecting the substance as the system passes through the stomach. Thus, these systems may not be suitable for orally delivering substances, such as viable bioactive microbial species, to the small intestine. The viability of some microbial species drops to 0% after 60 minutes in a buffer solution having a pH of 2. If the microbial species are not protected while passing through the stomach to the small intestine, some viable microbes may be destroyed in the stomach, which has a pH between 1 and 2.5 and a residence time of greater than 80 minutes. The high acidity and residence time of the stomach may render these orally deliverable substances as non-viable before reaching the small intestine. 
     Some systems use pH-sensitive polymers that can deliver substances immediately upon entry into the upper gastrointestinal tract, where the pH is approximately 5.8. However, these systems may result in lower viabilities for substances such as anaerobic microbes and may not be suitable for orally delivering these substances to lower downstream portions of the gastrointestinal tract such as the lower small intestine, the large intestine, or the colon. 
     SUMMARY 
     The present disclosure describes apparatus and methods relating to an ingestible, electrical device that delivers one or more substances to a gastrointestinal tract of an organism. In one aspect of the disclosure, an ingestible, electrical device comprises a substrate comprising a reservoir that is configured to hold one or more substances; a first film covering the reservoir, wherein the first film is at least partially metallic; a charge storage system connected to the first film, the charge storage system configured to deliver a transient electrochemical potential to the first film; wherein the first film is configured to prevent exposure of the substance to an aqueous environment in an organism, while the charge storage system delivers the transient electrochemical potential to the first film; and wherein the first film is configured for dissolution to expose the one or more substances to the aqueous environment in the organism, after the charge storage system stops delivering the transient electrochemical potential to the first film. 
     Implementations of the disclosure can include one or more of the following features. The substrate may include a bioexcretable copolymer. The bioexcretable copolymer may include at least one of polyester, polyanhydride, polyamide, polyether, polyphosphoester, polyorthoester, poly(ε-caprolactone) (PCL), or poly(ethylene glycol) (PEG). The ingestible, electrical device may include a second film serving as a counter electrode to the first film, wherein the second film is at least partially metallic, wherein each of the first film and the second film comprises at least one of iron, copper, gold, silver, or manganese, and wherein the first film dissolves at an increased rate, relative to a rate of dissolution of the second film. The first film may prevent exposure of the substance to the aqueous environment for an amount of time that is based on a thickness of the first film and an amount of charge stored in the charge storage device. A thickness of the first film may be less than 150 microns. The charge storage system may be configured to deliver the transient electrochemical potential in reverse bias to the first film. The charge storage system may be configured to deliver the transient electrochemical potential to the first film for a predetermined amount of time based on an amount of charge stored in the charge storage system. The first film may be configured for dissolution to expose the substance to the aqueous environment in the organism in a bolus release manner. The charge storage system may include a water-activated battery comprising one or more non-toxic biocompatible materials. The charge storage system may include a capacitor comprising one or more non-toxic biocompatible materials. The charge storage system may be configured to deliver a transient electrochemical potential greater than 0.5 volts to the first film for at least two hours. The substrate may include another reservoir configured to hold one or more additional substances; a second film may substantially cover the other reservoir; the second film may be configured to prevent exposure of the one or more additional substances to the aqueous environment in the organism, while the charge storage system delivers the transient electrochemical potential to the first film and the second film; and the second film may be configured for dissolution to expose the other substance to the aqueous environment in the organism, after the charge storage system stops delivering the transient electrochemical potential to the first film and the second film. The charge storage system may be connected to the first film using a physical connection. 
     In another aspect of the disclosure, a method comprises activating, based on exposure to an aqueous environment in an organism, a charge storage system of an ingestible, electrical device, the charge storage system being connected to a first film in the ingestible, electrical device, with a reservoir being covered by the first film, wherein the first film is at least partially metallic; following activation of the charge storage system, delivering a transient electrochemical potential from the charge storage system to the first film; while delivering the transient electrochemical potential from the charge storage system to the first film, preventing dissolution of the first film and exposure of the substance to the aqueous environment in the organism; ceasing to deliver the transient electrochemical potential from the charge storage system to the first film after a predetermined time; and following a cease in delivery of the transient electrochemical potential from the charge storage system to the first film, allowing the first film for dissolution to expose the substance to the aqueous environment in the organism. 
     Implementations of the disclosure can include one or more of the following features. A substrate may include the reservoir, wherein the substrate may include a bioexcretable copolymer. The bioexcretable copolymer may include at least one of polyester, polyanhydride, polyamide, polyether, polyphosphoester, polyorthoester, poly(ε-caprolactone) (PCL), or poly(ethylene glycol) (PEG). The charge storage system of the ingestible, electrical device is connected to a second film in the ingestible, electrical device that serves as a counter electrode to the first film, wherein the second film is at least partially metallic, wherein each of the first film and the second film comprises at least one of iron, copper, gold, silver, or manganese, and wherein the first film dissolves at an increased rate, relative to a rate of dissolution of the second film. The first film may prevent exposure of the substance to the aqueous environment for a specified amount of time that is based on a thickness of the first film and an amount of charge stored in the charge storage device. A thickness of the first film may be less than 150 microns. The transient electrochemical potential may be delivered in reverse bias to the first film. The predetermined amount of time may correspond to an amount of charge stored in the charge storage system. The first film may be configured for dissolution to expose the substance to the aqueous environment in the organism in a bolus release manner. The charge storage system may include a water-activated battery comprising one or more non-toxic biocompatible materials. The charge storage system may include a capacitor comprising one or more non-toxic biocompatible materials. The transient electrochemical potential may be greater than 0.5 volts and may be delivered for at least two hours. The ingestible, electrical device may include another reservoir for holding another substance, with the other reservoir being covered by a second film, and the method further may include while delivering the transient electrochemical potential from the charge storage system to the first film and the second film, preventing dissolution of the second film and exposure of the other substance to the aqueous environment in the organism; following the cease in delivery of the transient electrochemical potential from the charge storage system to the first film and the second film, allowing the second film for dissolution to expose the substance to the aqueous environment in the organism. The charge storage system may be connected to the first film using a physical connection. 
     In yet another aspect of the present disclosure, a device for delivering biologically active agents comprises a polycaprolactone substrate comprising a reservoir that is configured to hold a population of biologically active agents; a first film comprising iron and covering the reservoir; a water-activated battery comprising one or more non-toxic biocompatible materials, the water-activated battery connected to the first film, the water-activated battery configured to deliver a transient electrochemical potential greater than 0.5 volts to the first film for at least two hours; wherein the first film is configured to prevent exposure of the population of biologically active agents to an aqueous environment in a stomach of an organism while the water-activated battery delivers the transient electrochemical potential to the first film; and wherein the first film is configured to dissolve and expose the population of biologically active agents to an aqueous environment in an intestine of the organism after the charge storage system stops delivering the transient electrochemical potential to the first film. 
     The details of one or more implementations are set forth in the accompanying drawings and the description below. Other features, objects, and advantages will be apparent from the description, the drawings, and the claims. 
    
    
     
       BRIEF DESCRIPTION OF THE FIGURES 
         FIG. 1  shows an example of an ingestible, electrical device for delivering a substance to a gastrointestinal tract of an organism. 
         FIG. 2  shows an ingestible, electrical device during different stages of operation. 
         FIG. 3  shows a progression of an ingestible, electrical device through a gastrointestinal tract of an organism. 
         FIG. 4  is a flowchart of operations performed by an ingestible, electrical device to deliver a substance to a gastrointestinal tract of an organism. 
     
    
    
     DETAILED DESCRIPTION 
     An ingestible, electrical device consistent with this disclosure may include a microfabricated device that can deliver a substance to a specific portion of a gastrointestinal tract of an organism. The device may be orally administered and may reside in the gastrointestinal tract for several hours while protecting the substance from the strongly acidic environment in the stomach. The device can be configured to release the substance in a specific portion of the gastrointestinal tract in a bolus release manner based on an electronic cue that originates from the device without any external (extracorporal) trigger from outside the organism. The electronic cue activates one or more films or membranes to expose the contents contained in one or more reservoirs of the device. The electronic cue may be used to activate dissolution of the films and to control the dissolution rate of the films. 
     An ingestible, electrical device consistent with this disclosure can have a broad range of potential applications. For example, the device can be used in the treatment of metabolic and immunological diseases that may be caused by unbalanced microbiota populations occurring in a specific portion of the gastrointestinal tract. Microbiota populations in the gastrointestinal tract of a human may affect many aspects of human health, such as proper immunological function and metabolic homeostatis. Imbalanced gut flora, termed dysbiosis, may be a contributing factor to some diseases, such as type 1 and type 2 diabetes mellitus, obesity, inflammatory bowel disease, and atheroschlerosis. Non-pathogenic bacteria are essential components of a healthy metabolism as they aggregate pathogenic bacteria, secrete protective surfactants and enzymes, produce cytokines, serve as immunomodulators, and prevent colonization of pathogenic bacteria. Eubiosis, the healthy state of properly balanced gut microbiota, can limit nutrient uptake and reduce inflammation. Conversely, dysbiosis can contribute to both type 1 and type 2 diabetes by increasing nutrient uptake, insulin resistance, and proinflammatory cytokine profiles. 
     The device can be used for transplanting viable microbial populations to the specific portion of the gastrointestinal tract to balance microbiota, restore eubiosis, and recover metabolic health. The device may safely and effectively deliver viable probiotics to the intestines for treatment of diabetes, obesity, or both through therapeutic microbiota restoration in a cost-effective and minimally invasive manner. The device may prevent most viable microbes from being destroyed in the stomach, where the pH can be between 1 and 2.5 and the residence time can be greater than 80 minutes. The device can be used to administer synthetically engineered microbes that may exhibit increased pH sensitivity. 
       FIG. 1  shows an example of an ingestible, electrical device  100 . The device  100  may be packaged into an orally ingestible capsule that can be self-administered orally to a pediatric or an adult organism. The device  100  includes non-toxic biocompatible materials that can be absorbed, metabolized, or excreted by an organism, e.g., a human or other animal, that ingests the device  100 . The device  100  is non-toxic as defined by a maximum concentration that is non-toxic to the organism. The device  100  can deliver a bolus of one or more substances to any portion of the gastrointestinal tract with precise spatiotemporal control. 
     The device  100  may include a substrate  102 . The substrate  102  may include synthetic alpha-hydroxy polymers, crosslinked carbohydrates, polyesters, polyanhydride, polyamides, polyethers, polyphosphoesters, polyorthoesters, poly(ε-caprolactone) (PCL), or poly(ethylene glycol) (PEG). The substrate  102  may be fabricated using, for example, PCL by suitable 3D printing techniques. 
     The substrate  102  may be fabricated to include a hollow reservoir  104  for holding a substance  106 . The substance  106  can include any matter that would need protection from the caustic environment of the stomach as the device transits through the gastrointestinal tract. The substance  106  can include natural or synthetic viable biological matter. For example, the substance  106  can include a microbe composed of any combination of algae, bacteria, fungi, or yeast. As another example, the substance  106  can include biologically active agents such as proteins, antigens, vaccines, and adjuvants. Other examples of an orally deliverable substance include a virus or an eurkaryote. The substance may be loaded into the reservoir using micropipettes. 
     The reservoir  104  may be covered and sealed with a thin film  108 . In some implementations, another thin film  110  may be deposited on the substrate  102  in close proximity to the thin film  108  to serve as a counter electrode, or cathode, to the film  108  to coordinate dissolution (through, e.g., corrosion or erosion) of the film  108 , which serves as an anode. 
     In some implementations, the films  108  and  110  may be micropatterned metallic membranes deposited by thermal evaporation using shadow masks. Each of the films  108  and  110  may be deposited to have a thickness of less than 150 microns. In some implementations, the films  108  and  1100  may be fabricated on handling substrates and transferred to the PCL substrate  102  using microcontact printing. 
     Each of the films  108  and  110  may be at least partially metallic and include a noble metal such as iron, copper, gold, silver, or manganese, or any suitable combination of noble metals. Materials may be selected for the films  108  and  110  to coordinate galvanic corrosion of the films  108  and  110 , with the film  108  corroding at a faster rate than the film  110 . For example, the film  108  may include iron, and the film  100  may include copper. The films  108  and  110  may include other suitable materials devised for preprogrammed galvanic corrosion including water diffusion barriers. Electrolytic dissolution of the films  108  and  110  present negligible toxicity profiles to both the substance  106  and the organism ingesting the device  100 . 
     Corrosion rates of the films  108  and  110  may be based on the thickness of the films  108  and  110 . The corrosion rate of a thin film (e.g., a film having a thickness less than 150 microns) may be controllable and predictable, but the film alone may only be capable of protecting the substance from exposure on shorter time scales on the order of hours in a reliable time window. The corrosion rate of thicker films may extend the time line for corrosion, but the ability to predict the corrosion rate may become more difficult as the film becomes thicker due to pitting which can lead to uneven corrosion of metallic membranes. Corrosion behavior may also be a challenge to predict in biological environments that have proteins and aqueous solutions with high ionic strengths. 
     The device  100  may include a charge storage system  112  to control the onset of dissolution of the films  108  and  110 . The charge storage system  112  may provide a temporary electrochemical potential in reverse bias to the films  108  and  110  to temporarily stabilize the films  108  and  110 . When used in combination with appropriately selected materials for the films  108  and  110 , the charge storage system  112  can be used to control the dissolution rate of the films  108  and  110  and program the release time of the substance  106 . The exogenous potential supplied by the charge storage system  112  may delay the onset of dissolution of the films  108  and  110  in a predictable manner. Delaying the onset of dissolution of the films  108  and  110  may increase the specificity of the portion of the gastrointestinal tract in which the substance  106  will be released. Coupling the films  108  and  110  with the charge storage system  112  enables the ability to control the dissolution of the films  108  and  110  on long time scales (e.g., 10 to 20 hours). This long time scale may permit the delivery of microbiota, viruses, or other viable organisms to any region within the gastrointestinal tract. 
     The charge storage system  112  may be composed of non-toxic biocompatible materials that can be absorbed as nutrients or excreted as waste. The substrate  102  may be fabricated to contain relief features for electrodes  114  and  116  of the charge storage system  112 . The electrodes  114  and  116  and electrical contacts may be fabricated on handling substrates and transferred to the PCL substrate  102  using microcontact printing. In some implementations, the charge storage system  112  may be a water-activated battery. In some implementations, the charge storage system  112  may be a capacitor or a supercapacitor. 
     For example, the charge storage system  112  may be a water-activated battery composed of a sodium-loaded melanin anode and a lambda manganese oxide (λ-MnO 2 ) cathode. The electrical potential of melanin λ-MnO 2  batteries may be maintained for several hours. The applied potential of melanin batteries drops over time as the anode is discharged. The time (t 1 ) at which the battery can maintain a potential of |E|&gt;+0.7 volts can be adjusted by controlling the sodium (Na + ) loading. The battery may have sufficient storage capacity to delay the onset of dissolution of the films  108  and  110  for more than two hours (t 1 ). The corrosion time (t 2 ) of the film  108  can be controlled by selecting an appropriate thickness and material for the film  108 . 
     Iron anodes may be stable under an externally applied potential of |E|&gt;+0.5 V at a pH ranged of 1 to 9, which is within the range of gastric and intestinal fluids. Copper cathodes may be stable at all projected potentials supplied by the battery and across all pHs observed in the stomach and intestines. The battery&#39;s sodium loading and the film&#39;s material and thickness can be selected to control the delivery timeline for delivery of the substance  106  to specific portions of the gastrointestinal tract. The anodic and cathodic half-cell reactions for a pair of iron and copper films may be given as follows: Fe 2+ (aq)+2e-→Fe(s) (E anode =−0.41 V); Cu 2+ (aq)+2e-→Cu (s) (E cathode =+0.34 V). The voltage of the battery cell may be given by ΔV cell =E cathode −E anode =0.75 V. A reverse potential of this amount may confer galvanostatic protection to the iron film. This potential may define the voltage requirements for the charge storage system. 
     Although  FIG. 1  shows the device  100  having one reservoir  104 , an ingestible, electrical device may include multiple reservoirs for holding two distinct substances. The film that serves as the cathode, e.g., film  110  of device  100 , may also cover and seal a reservoir. The two distinct substances may be released at two different pre-programmed release times. The pre-programmed release times are based on delayed galvanic dissolution of the films, which are stabilized temporarily by applying a transient electrochemical potential in reverse bias. The prescribed charge capacity of the charge storage system determines the delay time before initiating corrosion of the films. The device may be designed for a two-phase release for delivery of one of the substances contained in one of the reservoirs to the upper gastrointestinal tract and the other of the substances contained in another reservoir to the lower gastrointestinal tract. For example, RFP+ E. Coli  bacteria can be delivered to the upper gastrointestinal tract, and GFP  E. Coli  bacteria can be delivered to the lower gastrointestinal tract. The charge storage system can be configured to release one of the substances after two hours following ingestion and the other substance after four hours following ingestion. These two release times may enable targeting of the upper small intestine and the lower small intestine. 
       FIG. 2  shows an ingestible, electrical device  200  during different stages of operation. At stages 1 and 2, a charge storage system  212  supplies a reverse bias that delays corrosion of an iron film  208  for a time period t 1  between two and twenty-four hours. After the delay period t 1  elapses, galvanostatic corrosion of the iron film  208  and the copper film  210  commences, and the film  208  begins to dissolve at stage 3. At stage 4, a substance  206  is delivered to the gastrointestinal tract of an organism after total dissolution of the film  208  at time t 2 . 
       FIG. 3  shows a progression of an ingestible, electrical device through a gastrointestinal tract  300  of an organism. The organism ingests the device where the device travels from an environment with a pH of 7.2 in the mouth (at position 1) to an environment with a pH of approximately 1 in the stomach  302  (at position 2). The low pH of the stomach  302  does not impact the oxidation potential of the iron film that covers the reservoir. The device will reside in the stomach  302  for approximately 90 minutes before passing to the small intestine  304  (position 3). As the device travels through the small intestine  304 , the electrical potential will drop as the battery becomes exhausted (at position 4). Corrosion of the iron film occurs and the substance is delivered after the corrosion time of the film has elapsed. 
       FIG. 4  is a flowchart of process  400  performed by an ingestible, electrical device, e.g., the ingestible, electrical device  100  of  FIG. 1 , to deliver a substance to a gastrointestinal tract of an organism. The operations include activating a charge storage system, e.g., a charge storage system  112  of the device  100  of  FIG. 1 , of the ingestible, electrical device ( 402 ). The activation of the charge storage system may be based on exposure to an aqueous environment in an organism. Following activation of the charge storage system, a transient electrochemical potential is delivered from the charge storage system to a first film, e.g., film  108  of device  100  of  FIG. 1 , and a second film, e.g., film  110  of device  100  of  FIG. 1  ( 404 ). While delivering the transient electrochemical potential from the charge storage system to the first film and the second film, dissolution of the first film and exposure of the substance to the aqueous environment in the organism is prevented ( 406 ). After a predetermined time corresponding to an amount of charge stored in the charge storage system, the transient electrochemical potential from the charge storage system ceases to be delivered to the first film and the second film ( 408 ). Following a cease in delivery of the transient electrochemical potential from the charge storage system to the first film and the second film, the first film is allowed for dissolution to expose the substance to the aqueous environment in the organism ( 410 ). 
     A number of implementations have been described. Nevertheless, various modifications can be made without departing from the spirit and scope of the processes and techniques described herein. In addition, the processes depicted in the figures do not require the particular order shown, or sequential order, to achieve desirable results. In addition, other steps can be provided, or steps can be eliminated, from the described processes, and other components can be added to, or removed from, the describe apparatus and systems. Accordingly, other embodiments are within the scope of the following claims.