WO2023034460A1 - Dispositif implanté pour libération de médicament à long terme - Google Patents

Dispositif implanté pour libération de médicament à long terme Download PDF

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Publication number
WO2023034460A1
WO2023034460A1 PCT/US2022/042272 US2022042272W WO2023034460A1 WO 2023034460 A1 WO2023034460 A1 WO 2023034460A1 US 2022042272 W US2022042272 W US 2022042272W WO 2023034460 A1 WO2023034460 A1 WO 2023034460A1
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WIPO (PCT)
Prior art keywords
assembly
cage
target site
biomaterial
bacteria
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PCT/US2022/042272
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English (en)
Inventor
Moshe Baruch
Laura Ortiz
John Wardle
Bonnie Wang
David Zhang
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Pana Bio, Inc.
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Publication date
Application filed by Pana Bio, Inc. filed Critical Pana Bio, Inc.
Publication of WO2023034460A1 publication Critical patent/WO2023034460A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin

Definitions

  • Drug delivery via either oral administration, subcutaneous injections, or intravenous injections/infusions will typically result in bolus pharmacokinetics and furthermore delivers the drug systemically throughout the body.
  • Systemic drug delivery may result in unintended effects in distant tissues from the target site of the disease.
  • Many patients who are diagnosed with chronic and/or localized diseases, such as inflammatory bowel disease would benefit from a medical device that is stable, programmable, reliable, allows for dosage control of therapeutic drugs, and provides both continuous and localized therapeutic drug delivery.
  • Drug-eluting stents can provide localized and continuous drug delivery in certain clinical settings and disease indications. However, these are limited to the circulatory system and exhibit limited programmability.
  • this disclosure provides for, and includes, a drug-eluting device comprising a porous, topologically closed cage encompassing one or more biomaterial particles encapsulating one or more therapeutic agents, wherein the device elutes a prophylactically or therapeutically effective amount of the one or more therapeutic agents when implanted in, at, or near a target site in a subject.
  • the one or more therapeutic agents as disclosed herein is selected from the group consisting of one or more small molecules, one or more biologics, and a combination thereof.
  • the one or more therapeutic agents as disclosed herein is selected from the group consisting of one or more microbes, one or more bacteria, and a combination thereof.
  • the one or more microbes or one or more bacteria as disclosed herein have been modified to produce or secret one or more small molecules and/or one or more biologics.
  • this disclosure provides for, and includes, an implantable, cell- encapsulation assembly comprising: (a) a device comprising a topologically closed chamber defined by (i) a perforated main body portion and (ii) two end portions, and (b) one or more biomaterial particles contained in the chamber encapsulating a first group of cells that, when implanted in, at, or near a target site in the subject, provide a desired therapeutic or prophylactic effect.
  • the device as disclosed herein further comprises an anchor for attachment to tissue in, at, or near the target site.
  • the perforated main body portion of the device as disclosed herein is tubular or substantially tubular.
  • the two end portions of the device as disclosed herein are different with one end portion further comprising an extension with an elastic coil configuration.
  • the biomaterial particles as disclosed herein comprise one or more biocompatible polymers.
  • the one or more biocompatible polymers as disclosed herein are synthetic polymers.
  • the first group of cells as disclosed herein comprises a microbial consortium comprising a mixture of two or more bacterial isolates.
  • the first group of cells as disclosed herein comprises two or more engineered bacterial isolates, each of which expresses one or more desired therapeutic agents which provide the desired therapeutic or prophylactic effect.
  • the first group of cells as disclosed herein sustains for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months after implantation.
  • this disclosure provides for, and includes, a drug-eluting device comprising: a porous, topologically closed cage with a maximum pore size of X, one or more biomaterial particles with a minimum diameter greater than Y, wherein at least 50% of the biomaterial particles comprise one or more therapeutic agents encapsulated within the interior of the particle, and where Y ⁇ X, and wherein the one or more therapeutic agents are formulated into a pharmaceutical composition further comprising one or more strains of bacteria, optionally bacteria are selected from a microbial consortium.
  • this disclosure provides for, and includes, a method for implanting a device or assembly, the method comprises: loading the device or the assembly into a lumen of an endoscope or catheter, navigating the tip of the endoscope or catheter to in, at, or near the target site, and deploying the device or the assembly in, at, or near the target site.
  • this disclosure provides for, and includes, a method for implanting a device or assembly, the method comprises: loading the device or the assembly over-the- scope to an endoscope, navigating the tip of the endoscope to in, at, or near the target site, and deploying the device or the assembly in, at, or near the target site.
  • this disclosure provides for, and includes, a method for implanting a device or assembly, the method comprises: loading the device or the assembly onto a laparoscopic instrument comprising a set of forceps, navigating the laparoscopic instrument to in, at, or near the target site, and deploying the device or the assembly in, at, or near the target site.
  • this disclosure provides for, and includes, a method for implanting a device or assembly, wherein the device or the assembly is attached in, at, or near the target site with a bioabsorbable suture.
  • this disclosure provides for, and includes, a method for implanting a device or assembly, the method comprises: loading the device or the assembly onto a guidewire, navigating the guidewire via fluoroscopy or ultrasound, and deploying the device or the assembly in, at, or near the target site.
  • this disclosure provides for, and includes, a method for treating or managing a gastrointestinal disease, the method comprising: implanting a device or assembly in, at, or near the target site via an endoscopic clip or suture, wherein the target site is in a gastrointestinal tract.
  • the gastrointestinal disease is selected from the group consisting of Crohn’s Disease, ulcerative colitis, pouchitis, toxic megacolon, short segment disease, chemotherapy-derived colitis, microscopic colitis, necrotizing colitis, Celiac disease, and proctitis, and wherein the therapeutic agents in the device or the assembly comprise one or more anti-inflammatory drug molecules.
  • the one or more anti-inflammatory drug molecules as disclosed herein comprise an anti-inflammatory cytokine.
  • the one or more anti-inflammatory drug molecules as disclosed herein comprise an antagonist for a pro-inflammatory cytokine.
  • the one or more anti-inflammatory drug molecules as disclosed herein comprise a monoclonal antibody.
  • the gastrointestinal disease is a chronic bacterial infection
  • the therapeutic agents in the device or the assembly comprise anti-microbial properties.
  • the chronic bacterial infection is selected from the group consisting of a C. difficile infection, a vancomycin-resistant Enterococcus infection, and an H. pylori infection.
  • this disclosure provides for, and includes, a method for treating or managing infections, wherein the infection is selected from the group consisting of a urinary tract infection, and a vaginal infection, the method comprising: implanting a device or assembly in, at, or near the target site via a catheter.
  • the therapeutic agents in the device or the assembly as disclosed herein are selected from the group consisting of anti-microbial peptides, anti-microbial small molecules, and a combination thereof.
  • the gastrointestinal disease is selected from the group consisting of intestinal fistula, peptic ulcer, and Graft vs. Host Disease, and wherein the therapeutic agents in the device or the assembly comprise one or more tissue repair drug molecules.
  • the one or more tissue repair drug molecules as disclosed herein comprise a cytokine.
  • Figure 1 depicts an illustration of one embodiment of the device.
  • the device comprises a porous cage with a mesh-like structure.
  • the cage encloses one or more hydrogel particles, and the particles comprise encapsulated drug molecules.
  • the pore size of the cage i.e., the diameter of the largest opening or hole in the mesh
  • the pore size of the cage is smaller than the diameter of the smallest hydrogel particle, so the particles are not able to escape the cage.
  • Figure 2 depicts an illustration of one embodiment of the usage of the device for the treatment of gastrointestinal diseases.
  • the device is implanted at or near the disease site.
  • the disease site is a portion of the transverse colon.
  • the drug molecules originally encapsulated in the hydrogel particles diffuse out of the hydrogel particles and cage and are released locally to the disease site.
  • the pharmacokinetics of the drug release can be controlled (e.g., delayed release or controlled release) via the total quantity and/or volume of the hydrogel particles, the density of the drug within the particles, and/or the material composition of the hydrogel particles.
  • Figure 3 depicts an illustration of one embodiment of the device with multiple species of hydrogel particles encapsulating different drug molecules.
  • FIG. 4 depicts an illustration of one embodiment of a method for manufacturing an embodiment of the device.
  • the cage is constructed through laser cutting and electropolishing a cylindrical tube as shown in Step 1.
  • Step 2 an end cap is affixed to one end of the mesh-like tube resulting from the cut cylinder.
  • Step 3 the hydrogel particles encapsulating drug molecules are loaded into the cage through one end.
  • Step 4 the second end cap is affixed, rendering the cage topologically closed and the hydrogel particles unable to escape without physical or mechanical damage.
  • Step 5 the completed device is sterilized, packaged, and stored until shipment or use.
  • the cage and the hydrogel particles are sterilized separately, and then sterilized particles are loaded into the sterilized cage.
  • Figure 5 depicts a computer-aided design (CAD) illustration of a device embodiment in which the linear cage is constructed from a laser-cut cylindrical tube. Multiple spherical hydrogel particles are arranged co-linearly inside the cage. In this embodiment, end caps prevent particle escape.
  • CAD computer-aided design
  • FIG. 6 depicts an illustration of one embodiment of the device in which the cage is constructed from a braided mesh. In this illustration, multiple suture wires are braided together to form the cage. In this embodiment, the cage is topologically closed to prevent hydrogel particle escape.
  • Figure 7 depicts a CAD illustration of a device embodiment in which the cage is constructed from a braided mesh. Multiple spherical hydrogel particles are arranged co- linearly inside the cage. In this embodiment, end caps prevent particle escape.
  • FIG. 8 depicts an illustration of deploying the device to an intestinal disease site via endoscopy.
  • the device is temporarily attached to the end of an endoscope and deployed into the lumen for attachment to the intestinal wall with an endoscopic clip or suture loop constructed from suture material.
  • the device and clip/suture loop are pushed through the lumen using endoscopy and guided to the intestinal disease site.
  • the clip or suture loop is deployed at or near the disease site and is attached to the mucosal layer of the intestinal wall.
  • the device is co-localized near the clip via the loop of suture material.
  • Figure 9 depicts an illustration of non-uniform drug density within the hydrogel particles.
  • the density of drug molecules is higher near the centroid of the spherical particle than near the surface of the particle.
  • higher concentrations of drug molecules towards the centroid of hydrogel particles results in more uniform drug release over time.
  • Figure 10 depicts an illustration of a device embodiment using a stent graft to affix the device to the disease site of interest.
  • the stent graft is affixed to one or a plurality of devices comprising the cage and the encompassed hydrogel particles with encapsulated drug molecules.
  • FIG. 11 depicts an illustration of a biomaterial particle embodiment encapsulating a plurality of cells of a specific bacterial strain within the hydrogel.
  • the bacteria can be uniformly dispersed throughout the hydrogel or be arranged non-uniformly.
  • colony forming units are used to quantify the number of individual bacteria cells in the hydrogel particles. CFUs are quantified by counting after the solution has been plated and grown under required environmental conditions on an appropriate agar.
  • Figure 12 depicts an illustration of a biomaterial particle embodiment encapsulating a plurality of cells of two bacterial strains within the hydrogel.
  • the number of individual bacteria cells in the hydrogel particles for each strain can either be equal or unequal to achieve the desired therapeutic effect.
  • CFUs are used to quantify the number of individual bacteria cells in the hydrogel particles. CFUs are quantified by counting after the solution has been plated and grown under required environmental conditions on an appropriate agar.
  • Figure 13A depicts an illustration of a drug molecule (e.g., either a small molecule and/or a biologic) being produced by one or more individual cells of a bacteria strain encapsulated within biomaterial particles.
  • a drug molecule e.g., either a small molecule and/or a biologic
  • the bacteria can be uniformly or non-uniformly dispersed throughout a pharmaceutical composition which further comprises one or more other drug molecules.
  • Figure 13B depicts an illustration of biomaterial particles encapsulating pharmaceutical compositions comprising a drug molecule and one or more bacteria strains that further produce one or more additional drug molecules.
  • Figure 14A depicts an illustration of two drug molecules (e.g., either small molecules and/or biologics) being produced by one or more individual cells of a bacteria strain encapsulated within biomaterial particles. In this embodiment, the amount of each drug molecule produced by the cell can either be equal or unequal to achieve the desired therapeutic effect.
  • Figure 14B depicts an illustration of biomaterial particles encapsulating pharmaceutical compositions comprising one or more drug molecules and one or more bacteria strains that further produce one or more additional drug molecules.
  • Figure 15 depicts an illustration of the CFU ratio between a plurality of bacteria strains over time. In this embodiment, the growth of bacteria in the biomaterial particle occurs, where the original CFU ratio between the bacteria strains is equal to the final CFU ratio. This maintains the therapeutic effect of the device as the bacteria react with the environment.
  • Figure 16 depicts a CAD illustration of a device embodiment in which the linear cage is constructed from braided materials which form a linear tube. The braided material terminates on each end of the cylindrical tube to allow for the attachment of end caps.
  • FIG. 17 depicts a CAD illustration of a device embodiment in which the cage forms a hollow, spiral tube. The spiral tube terminates on each end of the tube to allow for the attachment of end caps. The spiral cage and end caps enclose one or more hydrogel particles with encapsulated drug molecules.
  • Figure 18 depicts an illustration of one embodiment of the device in its relaxed state. In this embodiment, the device comprises a porous cage with a mesh-like structure 8.
  • FIG. 19 depicts an illustration of one embodiment of the device with a super- elastic coil 7 stretched into a straight configuration 14. The device can then be delivered to the target treatment site through an endoscope or catheter.
  • FIG. 20 depicts an exploded view of one embodiment of the device showing details and relationships of the various components used in the construction of the device.
  • Super-elastic coil wire 11 has an atraumatic ball end 12 and a straight section 15 which is co-axially engaged to the hole in the end cap 10.
  • a tubing 13 made from a biocompatible polymer such as polytetrafluoroethylene (PTFE) covers the super-elastic coil wire 11 and is captured between the ball end 12 and the endcap 10.
  • An optional suture 9 can be attached to the proximal endcap 10B by placing the suture in a loop passing it through the end cap hole and creating a knot at the end of the suture 9.
  • PTFE polytetrafluoroethylene
  • FIG 21 depicts a detailed view of the cage and the end cap 10.
  • the end cap(s) 10 which have snap-fit features 14 and 3 are used to securely join them to the cage.
  • Biologics can be introduced using the following method. Step 1, an end cap 10 is affixed to one end of the mesh-like tube resulting from the cut cylinder. In Step 2, the hydrogel particles with encapsulated drug molecules are loaded into the cage with one opening. In Step 3, the second end cap is affixed, rendering the cage topologically closed. The hydrogel particles are larger than the windows 5 in the cage rendering the hydrogel particles unable to escape without physical or mechanical damage.
  • the end cap(s) 10 that are attached to the cage have snap-fit features 14 and 3 which simply and securely retain them.
  • FIG. 22 depicts a CAD illustration of a device. In this case, the linear cage is longer (220 mm) and constructed from a cylindrical tube utilizing laser cutting, electropolishing, and heat setting processes.
  • Figure 23 depicts a CAD side view illustration of a device. In this case, the linear cage is longer and is constructed from a cylindrical tube utilizing laser cutting and electropolishing.
  • Figure 24 depicts a CAD front view illustration of the inwardly biased snap features 3 that retain the end caps.
  • Figure 25 depicts a CAD side view illustration of the inwardly biased snap features 3 that retain the end caps.
  • Figure 26 depicts a CAD flat pattern illustration of laser cutouts that are created in the device.
  • Figure 27 depicts a CAD detail view of the flat pattern illustration of laser cutouts that are created in the device. The inwardly biased snap feature 3 and windows 5 in the cage are illustrated.
  • Figure 28 depicts a CAD front view illustration of the heat set shape 6 that is finally created for the structure of the self-retaining cage.
  • Figure 29 depicts a perspective CAD illustration of the heat set shape 6 that is finally created for the structure of the self-retaining cage.
  • Figure 30 depicts a perspective CAD illustration of one embodiment of the end caps that are used on the terminal ends of the cage to topologically close the cage.
  • Figure 31 depicts a perspective CAD illustration of one embodiment of a cage structure constructed from a biocompatible alloy or polymer and surrounded by a protective cage, wherein the protective cage is fabricated from a stranded structure.
  • the cage has open spaces that can be altered to be optimized by changing the number of wires and or the pitch of the wind of the material and it can be sized to fit inside the endoscope instrument channel.
  • end caps may be present to provide topological closure to the ends of the cage or the ends may be welded closed.
  • FIG. 32 depicts a perspective CAD illustration of one embodiment of a cage structure that is constructed from a biocompatible alloy or polymer and is surrounded by a protective cage that is laser cut from tubing fabricated from a biocompatible material.
  • the cage has open spaces that can be altered to be optimized by modifying the laser-cut geometry.
  • the cage and associated components can be sized to fit inside the endoscope instrument channel.
  • end caps are welded to both ends of the laser-cut tube.
  • FIG. 33A, 33B, and 33C depicts three embodiments of attachment types.
  • the attachment site can be any target anatomical site in the individual organism. In other embodiments, the attachment is a different construction.
  • Figure 33A (top) depicts a spiral cage without end caps or attachment structures
  • Figure 33A (bottom) depicts a spiral cage equipped with two end caps and two polypropylene sutures, one on each terminus, each of which is attached through a hole in the end cap on the terminal portion of the cage.
  • the suture or sutures may be constructed from braided silk or other suture materials.
  • Figure 33B depicts an attachment structure that is constructed from polypropylene which is attached through a hole in the end cap on the linear portion of the cage.
  • the suture may be constructed from braided silk that is attached through a hole in the end cap on the linear portion of the cage.
  • Figure 33C depicts a suture attached to the endcap on the linear cage and the hemoclip.
  • Figure 34 depicts the process of producing an alginate noodle with encapsulated bacteria. Step 1, a cage or device is obtained with a single end sealed by (i) an end cap, (ii) welding, (iii) or another means of closure.
  • Step 2 the device and the uncured alginate and bacteria mixture are placed in a container.
  • Step 3 a cross-linking solution is added to the container with the uncured alginate and bacteria mixture.
  • the cross-linking solution facilitates the formation of the alginate noodle with encapsulated bacteria inside the device.
  • Figure 35A, 35B, and 35C depicts an example workflow from the production of the device through device implantation in mice. As shown in Figure 35B and 35C, the encapsulated bacteria can be frozen, stored, and shipped using appropriate methods.
  • DETAILED DESCRIPTION [0072] This description is not intended to be a detailed catalog of all the different ways in which the disclosure may be implemented, or all the features that may be added to the instant disclosure.
  • such degree of variation can be less than 0.1%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, between 1-2%, between 2-3%, between 3-4%, between 4-5%, or greater than 5% or 10%.
  • “about” can mean a variation of ⁇ 0.1%, ⁇ 0.5%, ⁇ 1%, ⁇ 2%, ⁇ 3%, ⁇ 4%, ⁇ 5%, ⁇ 6%, ⁇ 7%, ⁇ 8%, ⁇ 9% or ⁇ 10%.
  • any and all combinations of the members that make up that grouping of alternatives is specifically envisioned. For example, if an item is selected from a group consisting of A, B, C, and D, the inventors specifically envision each alternative individually (e.g., A alone, B alone, etc.), as well as combinations such as A, B, and D; A and C; B and C; etc.
  • the term “subject”, “individual”, or “patient” refers to a mammal ( ., rat, mouse, dog, cat, rabbit, mini-pig, pig, goats) capable of being (i) treated with the devices, assemblies, methods, and compositions of the disclosure, most preferably a human; or (ii) implanted with a device or an assembly disclosed herein such that the device or the assembly elutes one or more molecules of interest.
  • the subject is an adult human patient.
  • the subject is a pediatric human patient.
  • the subject is a nonhuman primate species (e.g., Macaca mulatta (rhesus monkey), M.
  • a device or an assembly described here may also be deployed in a fish, amphibian, or reptile.
  • the phrase “therapeutically effective amount” means an amount of a therapeutic, prophylactic and/or diagnostic agent that is sufficient, when administered to a subject suffering from or susceptible to a disease, disorder, and/or condition, to treat, prevent and/or diagnose the disease, disorder, and/or condition.
  • treating refers to (i) completely or partially inhibiting a disease, disorder or condition, for example, arresting its development; (ii) completely or partially relieving a disease, disorder or condition, for example, causing regression of the disease, disorder and/or condition; or (iii) completely or partially preventing a disease, disorder, or condition from occurring in a patient that may be predisposed to the disease, disorder and/or condition, but has not yet been diagnosed as having it.
  • treatment refers to both therapeutic treatment and prophylactic or preventative measures.
  • “treat” and “treating encompasses alleviating, ameliorating, delaying the onset of, inhibiting the progression of, or reducing the severity of one or more symptoms associated with the gastrointestinal disease.
  • “treat” and “treating encompasses alleviating, ameliorating, delaying the onset of, inhibiting the progression of, or reducing the severity of one or more symptoms associated with the urinary tract infection.
  • “treat” and “treating encompasses alleviating, ameliorating, delaying the onset of, inhibiting the progression of, or reducing the severity of one or more symptoms associated with the vaginal infection.
  • the term “managing” refers to improving the quality of life for individuals with a disease or disorder. It can also mean minimizing the effects, symptoms, or pathophysiological conditions through integrated medical care in subjects.
  • anchor refers to an attachment mechanism for attaching a device to a target site or anatomical location.
  • Example anchors include, e.g., hemoclip, endoscopic clip, clip, T-fastener, mechanical balloon, stent, and suture.
  • topologically closed in the context of a device described here, refers to the formation of a chamber or lumen that does not allow free transfer of biomaterial particles in and/or out of the chamber or lumen.
  • pore size refers to the size of each of the openings on a cage or chamber.
  • the terms “cage” and “chamber” are used interchangeably.
  • the terms “engineered” and “genetically modified” are used interchangeably.
  • the term “hydrogel” refers to a crosslinked hydrophilic polymer that does not dissolve in water. In an aspect, hydrogels are highly absorbent yet maintain well-defined structures.
  • hydrogel particle is a type of “biomaterial particle”.
  • target site refers to an anatomical region on the subject.
  • a target site, implantation site, or disease site is known to be diseased.
  • a target site or implantation site is a site of interest without a known disease.
  • a target site or implantation site is a site in, at, or near healthy tissue.
  • a target site or implantation site is associated with an anatomical feature on the subject’s body.
  • a target site is in the gastrointestinal tract of a subject.
  • a target site is in the urinary tract of a subject.
  • a target site is in the vagina of a subject.
  • biocompatible refers to a material that is substantially nontoxic to a recipient's cells in the quantities and at the location used, and also does not elicit or cause a significant deleterious or untoward effect on the recipient's body at the location used, e.g., an unacceptable immunological or inflammatory reaction, unacceptable scar tissue formation, etc..
  • the biocompatible material is naturally derived.
  • the biocompatible material is synthetic.
  • the biocompatible material is a polymer.
  • the biocompatible material is a synthetic polymer.
  • biodegradable or “bioabsorbable” means that a material is capable of being broken down physically and/or chemically within cells or within the body of a subject, e.g., by hydrolysis under physiological conditions and/or by natural biological processes such as the action of enzymes present within cells or within the body, and/or by processes such as dissolution, dispersion, etc., to form smaller chemical species which can typically be metabolized and, optionally, used by the body, and/or excreted or otherwise disposed of.
  • the biodegradable or bioabsorbable material is naturally derived.
  • the biodegradable or bioabsorbable material is synthetic.
  • the biodegradable or bioabsorbable material is a polymer. In an aspect, the biodegradable or bioabsorbable material is a synthetic polymer.
  • the phrase “microbial consortium”, also known as “bacterial cocktail” or “synthetic bacterial mixture”, refers to a mixture of bacteria comprising two or more bacterial isolates, and that the identity of each bacterial isolate in the cocktail is known, and thus the cocktail can be consistently produced (e.g., by combining isolated bacterial strains) to have a stable composition and properties across separate batches.
  • a microbial consortium comprises bacteria not genetically modified or engineered.
  • a microbial consortium comprises genetically modified or engineered bacteria.
  • a microbial consortium comprises a combination of bacterial isolates that are not genetically engineered and genetically engineered bacterial isolates.
  • drug molecules refers to any agent that, when administered to a subject, has a therapeutic, prophylactic and/or diagnostic effect and/or elicits a desired biological and/or pharmacological effect.
  • Drug molecules include, e.g., (i) a therapeutic molecule; (ii) a prophylactic molecule; (iii) a small molecule; (iv) a biologic molecule; (v) protein; (vi) nucleic acid; (vii) viral vector; (viii) other biomolecules that are related to human or veterinary medicine; and/or (ix) eukaryotic or prokaryotic cells.
  • colony forming unit refers to the measurement or quantification of the estimated number of bacteria or other microbial organisms in a sample.
  • a “small molecule” is understood in the art to be an organic molecule that is less than about 2000 g/mol in size.
  • the small molecule is less than about 1500 g/mol or less than about 1000 g/mol. In an aspect, the small molecule is less than about 800 g/mol or less than about 500 g/mol. In an aspect, small molecules are non- polymeric and/or non-oligomeric.
  • drug molecules encapsulated or embedded in the biomaterial or hydrogel particles are human biologic drugs ( Figure 1). For example, human biologic drugs, such as cytokines and monoclonal antibodies, can be used to treat a variety of diseases.
  • intravenous infusions are the most common delivery mechanism for these classes of therapeutics. Intravenous infusions, however, lead to high systemic concentrations of the biologic drug molecules and can cause adverse events in patients due to drug toxicity.
  • the presented device delivers the drug molecules locally to the disease site, minimizing the systemic concentration of the drug in the body and reducing adverse events.
  • the drug molecules are therapeutic agents other than human biologic drugs.
  • a single drug is delivered.
  • two or more drugs are delivered ( Figures 13 and 14).
  • the therapeutic agent delivered by the device may be a protein.
  • the therapeutic agent delivered by the device described here may be an immune system modulator or activator, e.g., a cytokine (e.g., IL- I, IL-la, IL-I , IL-IRA, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-12a, IL-12b, IL-13, IL-14, IL-16, IL- 17, G-CSF, GM-CSF, IL-20, IFN-a, IFN- , IFN-y, CD154, LT- , CD70, CD153, CD178, TRAIL, TNF-a, TNF- , SCF, M-CSF, MSP, 4-IBBL, LIF, OSM, and others.), anti-NGF, or antibodies.
  • a cytokine e.g., IL- I,
  • antibodies that may be produced or secreted by a cell include, for example, anti-PD-1, anti-PD-L1, anti-CTLA4, anti-TNFa, and anti-VEGF antibodies.
  • the antibody may be monoclonal or polyclonal.
  • the therapeutic agent delivered by the device is selected from the group consisting of an immune system modulator, an immune system activator, an antibody, a lipoprotein, an adhesion protein, a blood clotting factor (e.g., Factor VII, Factor VIII, Factor IX, GCG, or VWF), a hemoglobin, an enzyme, proenkephalin, a growth factor (e.g., EGF, IGF-1, VEGF alpha, HGF, TGF beta, bFGF), and a combination thereof.
  • a device described here delivers genetically modified bacteria.
  • the genetically modified bacteria are Escherichia coli spp ( Figure 13), e.g., Escherichia coli Nissle 1917.
  • the genetically modified bacteria are Limosilactobacillus (which was formerly defined as Lactobacillus) reuteri spp.
  • the genetically modified bacteria are from a strain of bacteria that is not Limosilactobacillus.
  • the device delivers bacteria that are not genetically modified or engineered.
  • the bacteria comprise two or more different strains, species, and/or genera ( Figures 12).
  • the bacterial strain(s) undergoes growth and increase the number of bacteria contained within the hydrogel ( Figure 15).
  • the bacterial strain(s) grow by binary fission.
  • the bacteria are a live therapeutic agent.
  • the bacteria are not a live therapeutic agent.
  • the bacteria provide a therapeutic effect in treating a disease, disorder, or condition.
  • the bacteria do not provide a therapeutic effect in treating a disease, disorder, or condition.
  • engineered bacteria may comprise multiple strains capable of communicating with each other.
  • engineered bacteria are selected from the group consisting of Escherichia coli, Lactobacillus reuteri, Lactobacillus crispatus, Lactobacillus rhamnosus, Lactobacillus crispatus, Lactococcus lactis, Bacteroides thetaiotamicron, Bacillus subtilis, and a combination thereof.
  • temperature-controlled storage and shipment do not affect the viability of bacteria.
  • storage at -80 o C does not impact the viability of bacteria stored in De Man, Rogosa, and Sharpe (MRS) agar and 25% glycerol for seven days ( Figure 35B and 35C).
  • a cell encompassed by the device described here is a human cell.
  • the cell is an engineered human cell (e.g., via gene editing or viral transduction) or a cell differentiated from induced pluripotent stem (iPS) cells.
  • the cell is a human cell without genetic modification.
  • the cell is a non-human animal cell.
  • the implanted cells are protected from a patient’s immune response and remain viable.
  • the implanted cells also are capable of producing therapeutic levels of the desired therapeutic agent for several hours, days, weeks, months, or years.
  • the device described here encapsulates cells (some are engineered) into semi-permeable biomaterial particles (e.g., hydrogel particles), such that the device and the biomaterial particles isolate the cells from the subject’s immune system cells while allowing entry of nutrients for the encapsulated cells and exit of the produced one or more therapeutic agents.
  • capsulation e.g., hydrogel
  • biomaterial particles contained in a device described here are made of hydrogel.
  • the hydrogel is comprised of an inner core and an outer shell.
  • the hydrogel is spherical in shape and conformation.
  • the hydrogel forms a noodle that is cylindrical in shape and conformation.
  • the biomaterial particles encompassed in the cage is in the form of an alginate noodle.
  • bacteria are encapsulated in the hydrogel.
  • the hydrogel is produced from 1.4% alginate.
  • the hydrogel is produced from a different percentage of alginate (e.g., 0.2-0.4%, 0.4-0.6%, 0.6-0.8%, 0.8-1.0%, 1.0-1.2%, 1.2-1.4%, 1.4-1.6%, 1.6-1.8%, 1.8-2.0%, 2.0-2.2%, 2.2-2.4%, 2.4-2.6%, 2.6-2.8%, 2.8-3.0%, 3.0- 3.2%, 3.2-3.4%, 3.4-3.6%, 3.6-3.8%, 3.8-4.0%, 0.2-4%, 0.4-3.6%, 0.6-3.2%, 0.8-2.8%, 1.0-2.4%, 1.2-2.0%, 1.4-1.8%).
  • hydrogel is produced from an inert material other than alginate.
  • hydrogel is produced from an inert synthetic material. In an aspect, hydrogel is produced from an inert natural material. [00109] In an aspect, the outer shell of the biomaterial particle or hydrogel particle is semi- or selectively permeable. In an aspect, drug molecules encapsulated in the hydrogel particle can diffuse across the selectively permeable outer shell of the hydrogel particle to enter the surrounding area. [00110] In an aspect, the hydrogel particle is produced from inert alginate or other inert substances that partially or fully surround the encapsulated bacteria ( Figure 11). In certain aspects, the hydrogel comprises nutrients. In an aspect, the hydrogen comprises carbon which can be used as a nutrient to support bacteria growth.
  • a biomaterial particle comprises a hydrogel comprising acrylated polyethylene glycol and another water-soluble non-cross-linkable polymer (e.g., polyethylene glycol, proteins, hyaluronic acid, collagen, polylysine, dextran, alginates, gelatin, elastin, cellulose, etc.).
  • another water-soluble non-cross-linkable polymer e.g., polyethylene glycol, proteins, hyaluronic acid, collagen, polylysine, dextran, alginates, gelatin, elastin, cellulose, etc.
  • the hydrogel comprises a cross-linkable protein or peptide (e.g., cross-linkable derivatives of elastin-like peptides, collagen- mimetic peptides, collagen-related peptides, polylysine) or a cross-linkable polysaccharide (e.g., cross-linkable derivatives of hyaluronic acid, methyl cellulose, dextran, alginate, etc.).
  • the hydrogel comprises a cross-linkable elastomeric polymer (e.g., cross-linkable derivative of poly glycerol sebacate).
  • the hydrogel comprises a cross-linkable peptide, protein, or polysaccharide which may include an acrylate moiety for cross-linking.
  • various polymers, molecular weights, extent of cross- linking, concentrations, cross-linkable moieties, and ratio of cross-linkable versus non- cross-linkable polymers may be utilized to produce the hydrogel.
  • the cross- linkable polymer component of the hydrogel is cross-linked using photo-crosslinking (e.g., using UV light).
  • the cross-linkable polymer component of the hydrogel is cross-linked using a free-radical reaction.
  • a free radical reaction may be initiated using light, heat, or a biological or chemical catalyst.
  • the free radical reaction is initiated using heat. In an aspect, the free radical reaction is initiated using light (e.g., UV light).
  • the hydrogel is biocompatible and is not readily biodegradable so that it has an extended half-life in vivo over hours, days, weeks, months, or years. Exemplary hydrogel particles can be found in U.S. Patent Publication No. US 2022/0000789 A1 and U.S. Patent No. US 8,802,153 B2. Further information can also be found in U.S. Provisional Application No.63/210,792. [00112]
  • any biomaterial particle can be used in accordance with the present disclosure.
  • biomaterial particles are biodegradable and biocompatible.
  • biomaterial particles are not toxic to cells.
  • biomaterial particles causes less than a certain threshold of cell death in the subject’s tissue after implantation of the device.
  • biomaterial particles do not induce adverse effects in the subject after implantation of the device.
  • biomaterial particles undergo breakdown under physiological conditions over the course of a therapeutically relevant time period (e.g., hours, days, weeks, months, or years).
  • biomaterial particles can be broken down by cellular machinery of the subject.
  • biomaterial particles can be broken down by chemical processes.
  • a biomaterial particle comprises a substance that is both biocompatible and biodegradable.
  • a biomaterial particle comprises a substance that is biocompatible, but not biodegradable.
  • a biomaterial particle comprises a substance that is biodegradable, but not biocompatible.
  • biomaterial particles are spheres, spheroids, flat, plate-shaped, cubes, cuboids, ovals, ellipses, cylinders, cones, or pyramids.
  • biomaterial particles comprise two or more distinct shapes.
  • biomaterial particles are irregularly shaped.
  • biomaterial particles are consistent in size.
  • biomaterial particles vary in size.
  • biomaterial particles are microparticles (e.g., microspheres).
  • biomaterial particles are nanoparticles (e.g., nanospheres).
  • biomaterial particles are liposomes.
  • biomaterial particles are micelles.
  • biomaterial particles are hollow and can comprise one or more layers (e.g., nanoshells, nanorings).
  • biomaterial particles are solid and can comprise one or more layers (e.g., nanoshells, nanorings).
  • a drug-eluting device described here comprises a porous, topologically closed cage encompassing one or more biomaterial particles.
  • the cage portion of the device can be significantly larger than the biomaterial or hydrogel particles so that a plurality of biomaterial or hydrogel particles are loaded into each cage.
  • the number, size, and drug density of the biomaterial or hydrogel particles loaded into the cage can be used to modulate the amount of drug delivered (Figure 9).
  • the biomaterial or hydrogel particles loaded into the cage are homogeneous in one or more characteristics selected from the group consisting of particle size, particle chemistry, particle geometry, drug content, drug concentration, and drug molecule distribution.
  • the biomaterial or hydrogel particles are homogeneous in drug content but heterogeneous in one or more characteristics selected from the group consisting of particle size, particle chemistry, particle geometry, drug concentration, or drug molecule distribution.
  • a cocktail of distinct hydrogel particles may enable the construction of a device with arbitrary desired drug release pharmacokinetics.
  • the biomaterial or hydrogel particles are heterogeneous in drug content but homogeneous in one or more characteristics selected from the group consisting of particle size, particle chemistry, and particle geometry.
  • the biomaterial or hydrogel particles allow for ratiometric delivery of different drug molecules in a desired predetermined ratio ( Figure 3).
  • the biomaterial or hydrogel particles are heterogeneous in drug content and heterogeneous in one or more characteristics selected from the group consisting of particle size, particle chemistry, particle geometry, drug concentration, and drug molecule distribution.
  • the biomaterial or hydrogel particles allow for phased delivery of different drug molecules in a pre-determined drug release order.
  • the cage has a drug coating.
  • the cage has a coating that prevents biofilm formation.
  • the cage has a coating to protect the anatomical structure of the subject. In an aspect, the cage does not have a coating.
  • the cage is fabricated through braiding a mesh of wires (Figure 6). In an aspect, the cage is fabricated through laser cutting a cylinder tube ( Figures 5, 22, 23, 26). In an aspect, the cage is electropolished. In an aspect, the cage is loaded with biomaterial or hydrogel particles encapsulating one or more therapeutic agents and then sealed using one or more end caps ( Figure 7). In an aspect, a sealed cage loaded with hydrogel particles encapsulating one or more therapeutic targets is sterilized to prevent bacterial contamination. In an aspect, sterilization is performed using ultraviolet light. In an aspect, the entire device has a self-retaining spiral shape.
  • the cage itself could be straight but be attached to a secondary self-retaining spiral-shaped wire with an over-tube that prevents erosion into the surrounding tissue of the implantation site ( Figure 4).
  • a device described here is spiral-shaped.
  • the unrestrained spiral-shaped feature of the device is larger than the anatomical space into which it is implanted.
  • the device is made from a super-elastic alloy, such as nitinol, which would allow the spiral to be uncurled out and then delivered to the treatment site via an endoscope or a delivery catheter.
  • the device when the device is ejected from the endoscope or catheter it attempts to open to its unrestrained shape but be prevented from doing so when it encounters the surrounding anatomy. In an aspect, when under compression, the device is retained by radial frictional forces.
  • the device comprises a closed wire loop topologically entangled with the cage.
  • the wire loop is made of a material suitable for suture wires.
  • the wire loop can be used to connect the device to other medical devices, such as endoscopic clips or pre-installed anchoring devices.
  • the device is affixed to the target or disease site via an endoscopic clip to secure the cage to the lumen of the gastrointestinal tract.
  • the device is attached to the target or treatment site with a suture.
  • the device is attached to the target or treatment cite with a bioabsorbable suture which is specifically designed to break down when the active life of the drug within the cage has lapsed.
  • the cage and its contents can be expelled from the body when the device is no longer attached to the target site.
  • the device is implanted via a catheter with a balloon expandable stent graft, which would expand to the diameter of the walls of the site ( Figure 10).
  • the device is implanted via a guidewire which can be guided to the treatment site via fluoroscopy or ultrasound imaging techniques.
  • the device is implanted during an open surgical procedure.
  • the device provides post- surgical site-specific therapy to the target site.
  • the device is attached to the target or treatment site with a bioabsorbable suture.
  • the bioabsorbable suture is specifically designed to break down when the active life of the drug within the cage has lapsed.
  • the cage and its contents are expelled from the body when the active life of the therapeutic agent within the case has lapsed.
  • the cage is self-retaining in, within, or inside of the target site.
  • a spiral or spring-shaped cage applies gentle force against the wall of the target anatomical site and remains in place ( Figures 28 and 29).
  • the cage is anchored in, within, or inside of the target site with sutures, hemoclips, T-fasteners, mechanical balloons, stents, other anchoring mechanisms, or a combination thereof.
  • a linear cage with an endoscopic clip is tethered to the target site by one, two, or more sutures.
  • the pore size within the cage can be selected to achieve a desired treatment effect.
  • large pore size allows an increased amount of diffusion of drug molecules from the cage to the target site.
  • small pore size allows only a minimum amount of drug molecules to diffuse from the cage to the target site.
  • pores can adopt various shapes such as (i) circular; (ii) ovoid; (iii) quadrilateral; (iv) rhomboid; (v) noncircular; or (vi) three-dimensional. In an aspect, pores adopt two or more distinct shapes.
  • one or more end caps are (i) deployed on both ends of the device; (ii) on one end of the device. In an aspect, at least one end of the device is welded shut. In an aspect, both ends of the device are welded shut. In an aspect, an end cap is deployed on one end of the device, and the other end is welded shut. In an aspect, some other means of closure of the device is used on one or both ends of the device.
  • diameter “A” as measured in the circular end cap is slightly smaller than the diameter of the circular terminal end on the cage ( Figure 24).
  • the end cap nests inside the terminal opening of the cage and is secured.
  • the end cap has clips that align and attach to the cage ( Figures 25 and 27).
  • the end cap has physical design features that allow for the end cap to be secured to the cage ( Figures 25 and 27).
  • the end caps are smaller than the diameter of the opening on the terminal end(s) of the cage ( Figure 21).
  • the end caps are different sizes and styles that promote topological closure of the cage.
  • the end caps are (i) solid ( Figure 21); (ii) solid on the end with a mesh construction on the body of the end cap ( Figures 25 and 27); (iii) or completely mesh.
  • a device and/or biomaterial particles contained therein are biocompatible and/or biodegradable. vice manufacturing
  • the materials for the construction of the cage 8 and or the super-elastic coil 7 (retaining coil 7) have super-elastic properties.
  • One material that exhibits this property is nitinol (NiTi), a shape memory alloy made of nickel and titanium in almost equal concentrations. A shape memory alloy can restore its original shape after deformation.
  • Nitinol Used frequently for the construction of medical devices, Nitinol is popular due to its super-elasticity and fatigue and kink resistance. Nitinol is used to manufacture stents, glaucoma drainage devices implants, catheter tubes, guidewires, stone retrieval baskets, and other surgical instruments. In an aspect, the cage is constructed completely or partially from nitinol. In an aspect, the super-elastic coil or retaining coil is constructed completely or partially from nitinol. [00124] Nitinol is also biocompatible. When nitinol implants receive appropriate surface treatment through electropolishing and passivation, they develop a passive titanium oxide layer, which forms a barrier that prevents corrosion. Super-elasticity and high strain accommodation are also beneficial in endoscopic applications.
  • the device is attached to the end of an endoscope and deployed for attachment in, at, or near the target site ( Figure 8).
  • the device is attached to the endoscope by a clip.
  • the device and endoscopic clip are pushed through the lumen using the endoscope.
  • the clip is deployed by the endoscope operator and the clip(s) is attached to the target anatomical site (e.g., intestinal wall).
  • the device is affixed to the target site via radial expansion alone.
  • the device is affixed to the disease site via radial expansion and an endoscopic clip to secure the cage to the lumen of the gastrointestinal tract.
  • the spiral-shaped feature of the device can be collapsed after deployment or its useful life allowing it to be removed from the patient using an endoscope or catheter.
  • the devices comprise a porous, topologically closed cage, one or more hydrogel biomaterial particles enclosed by the cage, and a set of drug molecules encapsulated within the particles (Figure 1).
  • the hydrogel particles have a diameter that is larger than the pore size of the cage, thus preventing the escape of the particles from the cage.
  • the drug molecules encapsulated in the hydrogel particles diffuse out of the hydrogel and escape the cage.
  • the devices are intended for implantation for more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 32, 48 or 56 weeks, more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or more than 1, 2, 3, 4, 5, 6, 7 or 8 years.
  • the cage is non-expanding. In an aspect, the cage is flexible.
  • the device is implanted within a subject’s body via other medical devices, such as endoscopes, endoscopic clips, stent-grafts, or catheters. The benefit of this device is that it allows long-term release of the drug molecules locally at an implantation site, which in some embodiments is a disease site.
  • the disease is inflammatory bowel disease, and the implantation site comprises the small intestine or the large intestine ( Figure 2).
  • the disease is not inflammatory bowel disease.
  • the disease is a gastrointestinal disease.
  • the disease is a urinary tract infection.
  • the disease is a vaginal infection. In an aspect, the disease is a chronic bacterial infection.
  • the device provides localized and continuous delivery of drug molecules encapsulated in the biomaterial or hydrogel particles. In an aspect, the device provides localized and continuous delivery of therapeutic agents encapsulated in the biomaterial or hydrogel particles. In an aspect, the device provides localized and continuous delivery of non-drug molecules encapsulated in the biomaterial or hydrogel particles. In an aspect, the device provides localized and continuous delivery of other types of molecules. [00132] In an aspect , the device provides delivery of drugs at the appropriate recommended dosage.
  • the dosage is a weight/volume (w/v) selected from the group consisting of ⁇ 5 mg/volume, between 5 and 10 mg/volume, 10 mg/volume, 15 mg/volume, between 10 and 100 mg/volume, 20 mg/volume, 25 mg/volume, 30 mg/volume, 35 mg/volume, 40 mg/volume, 45 mg/volume, 50 mg/volume, 55 mg/volume, 60 mg/volume, 65 mg/volume, 70 mg/volume, 75 mg/volume, 80 mg/volume, 85 mg/volume, 90 mg/volume, 95 mg/volume, 100 mg/volume, and > 100 mg/volume.
  • w/v weight/volume
  • the treatment comprises using the device to administer a continuous pharmaceutically active dose of a therapeutic agent to a subject in need thereof for ⁇ 1 month, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or > 12 months.
  • the treatment comprises using the device to administer a continuous dose of drug molecules to a subject in need thereof for ⁇ 1 month, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or > 12 months.
  • the treatment comprises using the device to administer a continuous dose of non-drug molecules to a subject in need thereof for ⁇ 1 month, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or > 12 months.
  • the treatment achieves at least a 10% reduction in disruption of the mucosal lining of the intestine in a subject. In an aspect, the treatment achieves more than 10% reduction in disruption of the mucosal lining of the intestine in a subject.
  • EXAMPLES ample 1 Exemplary cage design for a drug-eluting device. [00137] A device cage is made essentially following the workflow as described in Figure 4.
  • the cage is made from nitinol tubes which are laser cut (by Meko) and electro-polished to remove sharp edges and ensure proper closure. There are no special coatings. After removal from the electropolishing bath, exposure to the atmosphere causes a titanium oxide layer to form on the surface of the cage which makes the device highly biocompatible.
  • a braided cage is also made ( Figures 6 and 7). This cage is made from braided biocompatible alloy or polymer and its ends are sealed by pulling together Braid’s filers and welded shut.
  • Three different designs are explored for the porous cage.
  • the first design (V2 and V3) uses a linear cage ( Figure 16).
  • the linear devices have sutures from both ends, which allow anchoring the device to the colon wall.
  • Anchoring the device from both sides helps prevent free movement of the device in the lumen of the colon and helps to keep the device close to the colon wall to allow efficient administration of the therapeutic agent (e.g., drug) to the targeted site.
  • the anchoring of the device is achieved using different strategies such as stitching the one or more end to the intestinal wall or clamping the one or more ends to the intestinal wall using an endoscopic clip.
  • the second design uses a cage with a spiral or spring shape (Figure 17). To obtain the spring shape, a 220 mm linear cage is placed in a heat setting tool (3D printed tool made by Meko) and then the cage in the device was heat treated. More details are shown in Figures 18 to 29.
  • the third design is based on the linear cage design (V3; Figure 16) except it has a coiled nitinol wire at one of the ends of the device to form a spiral or spring shape ( Figures 18 and 19).
  • the coiled nitinol is attached to the end cap of the device and is designed to keep the cage in the nearest proximity to the wall of the colon or intestine.
  • An anchor-like surgical suture or other attachment structures are installed on one end of the device.
  • On the end opposite the attachment structure there is a spring-shaped wire that is designed to be a tube the size and shape of the colon wall of the vertebrate animal. This design generates gentle pressure against the wall of the intestine to prevent free movement or displacement of the device in the intestine.
  • the device may be anchored.
  • the anchoring of the device is achieved using different strategies such as stitching one or more ends to the intestinal wall or clamping the one or more ends to the intestinal wall using an endoscopic clip.
  • the coiled nitinol wire is coated with Teflon tubing to thicken the overall wire diameter and to construct a smooth interface between the wire and the colon wall ( Figure 20). This design prevents possible trauma or stress to the surrounding tissue which may be caused by pressing a thin, metal wire on the colon wall without the Teflon tubing.
  • spring-like wires are attached to one end of the device ( Figure 18).
  • the spring-like shape of the wires is constructed by restraining the wire and producing the spring-like shape using a mandrel or related device. Afterward, the wire component and mandrel are placed in a pre-heated furnace at 505 o C. After five minutes at 505 o C in the furnace, the wire component and mandrel are removed and quenched in a water bath to set the spring-link shape. [00144] In the third design (V5), the wire diameter, the spring-shaped features, and the Teflon tube thickness are varied and dependent on the properties of the diameter of the colon, intestine, or other target implantation sites. ample 2: Exemplary end cap design.
  • the end caps are constructed from titanium, titanium alloy, or other biocompatible material (Figure 30).
  • Figure 30 there are no end caps for the terminal ends of the cage. Instead, one or both terminal ends of the cage are welded shut. This type of topological enclosure may only be done with a cage design based on a braid-cage made from biocompatible alloy, polymer, or other biocompatible material ( Figure 31).
  • Figure 32 the end caps for the terminal ends of the cage are welded to one or both terminal ends of the cage in a braid-constructed cage.
  • the end caps for the terminal ends of the cage are constructed with nested clips that unite and are attached to specialized indentations located on the cage ( Figures 23 and 25). These nested clips securely attach to the specialized indentation locations on the cage to provide topological closure to the content of the cage. ample 3: Attachment of clips to the cage.
  • braided silk or polypropylene is used to directly attach the hemoclip to the cage by making a loop in one or both end caps of the device ( Figure 18). The hemoclip attaches the loop and the organism’s tissue to enable anchoring of the device in the target anatomical location.
  • end caps are used to topologically close the cage, and there is a hole or opening in the center of one or both end caps for the suture or other biomaterials to pass through the one or both end caps and be tied at the other end.
  • the tie is larger than the hole or opening in the end cap to ensure that the suture or the other materials remains in place and is attached to the end cap ( Figure 33A, 33B, and 33C).
  • braided silk or polypropylene sutures are used to attach the hemoclip ( Figure 33A, 33B, and 33C).
  • a biocompatible alloy or metal loop is used to attach the hemoclip, suture, or other attachment structure ( Figure 5).
  • the attachment material can be constructed from any rigid biocompatible material, including, but not limited to (i) silicone-based materials, (ii) plastic(s), (iii) polymers, (iv) alloys, or (v) a three-dimensional (3D) printed biocompatible component.
  • a stent graft is used to attach the cage using biocompatible wires ( Figure 10).
  • the attachment material can be constructed from any rigid biocompatible material.
  • the end caps are (i) deployed on both ends of the device; (ii) on one end of the device and the other end is welded shut; (iii) are not used and both ends are welded shut; or (iv) are not used and some other means of closure are used.
  • an end cap is affixed to one end of the mesh-like tube resulting from the cut cylinder.
  • the hydrogel particles encapsulating the drug molecules are loaded into the cage with one opening.
  • the second end cap is affixed, rendering the cage topologically closed and the hydrogel particles unable to escape without physical or mechanical damage (Figure 4).
  • a braided mesh cage is topologically closed with Braid’s filer and welded shut.
  • end caps are not used to topologically close the cage.
  • Bacteria can be encapsulated directly inside the cage by first sealing one end of the device using (i) an end cap or (ii) by means of welding. The partially sealed device is then placed in a curing solution with the unsealed end facing upwards. The alginate is directly combined with the bacteria. The alginate-bacteria mix is injected into the open space of the device using an appropriate needle or tubing with a slightly smaller diameter than the device. This size difference allows for the needle or tubing to slide into the open space of the device.
  • the alginate-bacteria mix is injected it immediately cures to form a continuous noodle-shaped biogel in the device. Once the injection method is complete, seal the open end of the device. If a sterile alginate coating layer is desired around the noodle to make a shell layer, the device is submerged in uncured alginate solution and subsequently placed in a curing bath. This step is repeated until the desired shell layer thickness is achieved (Figure 34). ⁇ ample 5. Encapsulation of bacteria, homogenization of biomaterial particles, shipping,d storage [00158] In this design, a hydrogel is produced from 1.4% alginate and used to encapsulate bacteria in the inner core of the hydrogel.
  • the bacteria are encapsulated in the inner core of the hydrogel using a crosslinking agent.
  • the outer shell of the hydrogel is formed to encapsulate the inner core containing the bacteria using a crosslinking agent ( Figure 11).
  • the final encapsulated hydrogel particles are washed in buffer and stored at -80 o C in freezing buffer.
  • ethylenediaminetetraacetic acid (EDTA) is combined with hydrogel particles and homogenized using an electric homogenizer. The homogenized solution is immediately placed in sterile saline, serially diluted, and plated on appropriate agar plates. Colony forming units are quantified.
  • the encapsulated bacteria can be stored at -80 o C in freezing buffer in a volume of freezing buffer that is at least five times the volume of the hydrogel particles.
  • Freezing buffer is a sterile solution of De Man, Rogosa, and Sharpe (MRS) agar and glycerol.
  • the freezing buffer and hydrogel particles can undergo slow defrosting at room temperature (Figure 35B and 35C).
  • the alginate-bacteria mix is injected into the open space of the device using an appropriate needle or tubing with a slightly smaller diameter than the device. This size difference allows for the needle or tubing to slide into the open space of the device. Once the alginate-bacteria mix is injected it immediately cures to form a continuous noodle-shaped biogel in the device. Once the injection method is complete, the open end of the device is sealed. [00163] If a sterile alginate coating layer is desired around the noodle to make a shell layer, the device can be submerged in uncured alginate solution and subsequently placed in a curing bath. This step is repeated until the desired shell layer thickness is achieved (Figure 34). ample 7: Implantation of a device in the intestine.
  • the device is delivered to the target site through an endoscope, colonoscope, gastroscope, or catheter.
  • the device is loaded into the catheter or endoscope channel.
  • the loaded catheter or endoscope is deployed (pushed out) to the implantation site using a flexible rod or delivery sleeve.
  • the deployment of the device begins after the endoscope or catheter is in, at, or near the implantation site ( Figure 8).
  • ample 8 Attaching a device to the intestine for long-term treatment.
  • the device can be secured to the target site via sutures. Over-stitching is one way to secure the device to the surrounding tissue. Loose suture(s) are made at the implantation site.
  • the device is attached to the suture(s) using a hemoclip attached to the device.
  • the device can be secured to the target site via hemoclip.
  • a hemoclip is attached to the device and can attach to the surrounding tissue ( Figure 33C).
  • the device can be secured to the target site via a T-fastener or gastrointestinal anchor (Imakita et al., Colonoscopy-assisted percutaneous sigmoidopexy: a novel, simple, safe, and efficient treatment for inoperable sigmoid volvulus (with videos). Gastrointestinal Endoscopy, 90(3): 514-520 (2019)).
  • the T-fastener has two components, including a metal bar that is inside the implantation site and a component that works like an anchor that stays on the outside of the organism.
  • a device is a self-retaining device and remains in the target site because of gentle radial force that the spring-like shape of the device exerts on the surrounding tissue ( Figures 18, 28, and 29).
  • ample 9 Example of animal experiment using rodents.
  • rodents are orally gavaged with the bacteria encapsulated within the biomaterial or hydrogel particles.
  • rodents are subcutaneously injected with the bacteria encapsulated within the biomaterial or hydrogel particles.
  • rodents have chemically induced colitis and receive treatment with the therapeutic agents encapsulated in the biomaterial or hydrogel particles.
  • rodents have genetically induced colitis and receive treatment with the therapeutic agents encapsulated in the biomaterial or hydrogel particles.
  • rodents have T-cell adoptive colitis and receive treatment with the therapeutic agents encapsulated in the biomaterial or hydrogel particles.
  • rodents have a drug-device combination implanted in a target anatomical site. For example, rats have an IL-10-releasing device endoscopically implanted in the large intestine.
  • histopathological analysis to score inflammation of the anatomical site is conducted using a 0 to 3 scoring scheme, where a score of 0 is equal to healthy, a score of 1 is equal to mild inflammation, a score of 2 is equal to moderate inflammation, and a score of 3 is equal to severe inflammation.
  • the disease activity index is used to characterize the clinical progression of colitis using a scoring system, where a score of 0 is characterized by no weight loss experienced, no blood in stool, and feces with normal consistency; a score of 1 is characterized by 1-5% weight loss, no visible blood in stool, but positive hemoccult test, and loose/soft stool; a score of 2 is characterized by 5-10% weight loss, positive hemoccult test, visual blood in stool, and very soft stool; a score of 3 is characterized by 10-15% weight loss, blood around the anus and prolapse, and mildly watery stool; and a score of 4 is characterized by 15-20% weight loss, gross bleeding, and diarrhea.
  • the infiltrating immune cell composition is characterized using cytometry by time of light analysis. Single cells are stained with a panel of 40 antibodies that are used to characterize the immune response. For example, mature dendritic cells and regulatory T cells are observed to be in the acceptable range as identified for subjects with a non-inflamed large intestine. ample 10: Example of animal experiment using canines. [00173] In one experiment, canines are orally gavaged with the bacteria encapsulated within the biomaterial or hydrogel particles. In one experiment, canines are subcutaneously injected with the bacteria encapsulated within the biomaterial or hydrogel particles.
  • canines have chemically induced colitis and receive treatment with the therapeutic agents encapsulated in the biomaterial or hydrogel particles.
  • canines have genetically induced colitis and receive treatment with the therapeutic agents encapsulated in the biomaterial or hydrogel particles.
  • canines have T-cell adoptive colitis and receive treatment with the therapeutic agents encapsulated in the biomaterial or hydrogel particles.
  • canines have a drug-device combination implanted in a target anatomical site. For example, mongrel dogs have an IL-10-releasing device endoscopically implanted in the large intestine.
  • histopathological analysis to score inflammation of the anatomical site is conducted using a 0 to 3 scoring scheme, where a score of 0 is equal to healthy, a score of 1 is equal to mild inflammation, a score of 2 is equal to moderate inflammation, and a score of 3 is equal to severe inflammation.
  • the disease activity index is used to characterize the clinical progression of colitis using a scoring system, where a score of 0 is characterized by no weight loss experienced, no blood in stool, and feces with normal consistency; a score of 1 is characterized by 1-5% weight loss, no visible blood in stool, but positive hemoccult test, and loose/soft stool; a score of 2 is characterized by 5-10% weight loss, positive hemoccult test, visual blood in stool, and very soft stool; a score of 3 is characterized by 10-15% weight loss, blood around the anus and prolapse, and mildly watery stool; and a score of 4 is characterized by 15-20% weight loss, gross bleeding, and diarrhea.
  • the infiltrating immune cell composition is characterized using cytometry by time of light analysis. Single cells are stained with a panel of 40 antibodies that are used to characterize the immune response. For example, mature dendritic cells and regulatory T cells are observed to be in the acceptable range as identified for subjects with a non-inflamed large intestine. ample 11: Example of animal experiment using porcine. [00177] In one experiment, porcine are orally gavaged with the bacteria encapsulated within the biomaterial or hydrogel particles. In one experiment, porcine are subcutaneously injected with the bacteria encapsulated within the biomaterial or hydrogel particles.
  • porcine have chemically induced colitis and receive treatment with the therapeutic agents encapsulated in the biomaterial or hydrogel particles.
  • porcine have genetically induced colitis and receive treatment with the therapeutic agents encapsulated in the biomaterial or hydrogel particles.
  • porcine have T-cell adoptive colitis and receive treatment with the therapeutic agents encapsulated in the biomaterial or hydrogel particles.
  • porcine have a drug-device combination implanted in a target anatomical site. For example, pigs have an IL-10-releasing device endoscopically implanted in the large intestine.
  • histopathological analysis to score inflammation of the anatomical site is conducted using a 0 to 3 scoring scheme, where a score of 0 is equal to healthy, a score of 1 is equal to mild inflammation, a score of 2 is equal to moderate inflammation, and a score of 3 is equal to severe inflammation.
  • the disease activity index is used to characterize the clinical progression of colitis using a scoring system, where a score of 0 is characterized by no weight loss experienced, no blood in stool, and feces with normal consistency; a score of 1 is characterized by 1-5% weight loss, no visible blood in stool, but positive hemoccult test, and loose/soft stool; a score of 2 is characterized by 5-10% weight loss, positive hemoccult test, visual blood in stool, and very soft stool; a score of 3 is characterized by 10-15% weight loss, blood around the anus and prolapse, and mildly watery stool; and a score of 4 is characterized by 15-20% weight loss, gross bleeding, and diarrhea.
  • the infiltrating immune cell composition is characterized using cytometry by time of light analysis. Single cells are stained with a panel of 40 antibodies that are used to characterize the immune response. For example, mature dendritic cells and regulatory T cells are observed to be in the acceptable range as identified for subjects with a non-inflamed large intestine.
  • ample 12 Example of animal experiment using non-human (i.e., near human) primates.
  • non-human (i.e., near human) primates are orally gavaged with the bacteria encapsulated within the biomaterial or hydrogel particles.
  • non-human primates are subcutaneously injected with the bacteria encapsulated within the biomaterial or hydrogel particles.
  • non-human primates have chemically induced colitis and receive treatment with the therapeutic agents encapsulated in the biomaterial or hydrogel particles.
  • non-human primates have genetically induced colitis and receive treatment with the therapeutic agents encapsulated in the biomaterial or hydrogel particles.
  • non-human primates have T-cell adoptive colitis and receive treatment with the therapeutic agents encapsulated in the biomaterial or hydrogel particles.
  • non-human primates have a drug-device combination implanted in a target anatomical site. For example, cynomolgus monkeys have an IL-10- releasing device endoscopically implanted in the large intestine.
  • the disease activity index is used to characterize the clinical progression of colitis using a scoring system, where a score of 0 is characterized by no weight loss experienced, no blood in stool, and feces with normal consistency; a score of 1 is characterized by 1-5% weight loss, no visible blood in stool, but positive hemoccult test, and loose/soft stool; a score of 2 is characterized by 5-10% weight loss, positive hemoccult test, visual blood in stool, and very soft stool; a score of 3 is characterized by 10-15% weight loss, blood around the anus and prolapse, and mildly watery stool; and a score of 4 is characterized by 15-20% weight loss, gross bleeding, and diarrhea.
  • the infiltrating immune cell composition is characterized using cytometry by time of light analysis. Single cells are stained with a panel of 40 antibodies that are used to characterize the immune response. For example, mature dendritic cells and regulatory T cells are observed to be in the acceptable range as identified for subjects with a non-inflamed large intestine. emplary Embodiments [00185] A variety of further modifications and improvements in and to the devices, assemblies, methods, and compositions of the present disclosure will be apparent to those skilled in the art. The following non-limiting embodiments are envisioned. [00186] Embodiment 1.
  • a drug-eluting device comprising: a porous, topologically closed cage with a maximum pore size of X, one or more biomaterial particles with a minimum diameter greater than Y, wherein the biomaterial particles comprise drug molecules encapsulated within the interior of the particles, and where Y ⁇ X.
  • Embodiment 2 The device of Embodiment 1, wherein the maximum pore size X of the closed cage is selected from the group consisting of approximately or less than 1 mm, approximately or less than 0.5 mm, approximately or less than 0.2 mm, approximately or less than 0.1 mm, approximately or less than 50 ⁇ m, approximately or less than 20 ⁇ m, and approximately or less than 10 ⁇ m.
  • Embodiment 2 wherein the closed cage has a geometry selected from the group consisting of an approximately cylindrical, approximately spherical, approximately rectangular prism, approximately conical, approximately helical, approximately spiral, and approximately serpentine.
  • Embodiment 4. The device of any of Embodiments 2-3, wherein the closed cage comprises at least one region that is welded shut.
  • Embodiment 5. The device of any of Embodiments 1-4, wherein the cage material is selected from the group consisting of medical grade stainless steel, cobalt- chromium alloys, platinum, nitinol, and titanium. [00191] Embodiment 6.
  • the cage material is selected from the group consisting of medical grade polymers, isobutyl cyanoacrylate (IBCA), n-butyl cyanoacrylate (NBCA), polymethyl methacrylate (PMMA), polyvinyl alcohol (PVAL), ethylene vinyl alcohol (EVAL), silicone, cellulose acetate (CA), polyether ether ketone (PEEK), and polyester.
  • IBCA isobutyl cyanoacrylate
  • NBCA n-butyl cyanoacrylate
  • PMMA polymethyl methacrylate
  • PVAL polyvinyl alcohol
  • EVAL ethylene vinyl alcohol
  • silicone cellulose acetate
  • CA polyether ether ketone
  • polyester polyester
  • Embodiment 9 The device of any of Embodiments 1-7, wherein the cage is coated with material to prevent biofouling, selected from the group consisting of material to prevent biofilm formation, and material to prevent fibrotic foreign body response, such as chelators, anti-virulence compounds, anti-biofilm compounds, N-acetylcysteine, polymer brush coatings, submicron surface textures, and antibiotics.
  • Embodiment 9 The device of any of Embodiments 1-8, wherein the cage is coated with a drug, such as an anti-virulence compound, antibiotic, or biologic.
  • Embodiment 10 The device of any of Embodiments 1-9, wherein the cage comprises a radiopaque component.
  • Embodiment 10 wherein the radiopaque component comprises a precious metal selected from the group consisting of gold, platinum, tantalum, and palladium.
  • Embodiment 12 The device of Embodiment 1, wherein the minimum diameter Y of the biomaterial particles is selected from the group consisting of approximately or more than 1 mm, approximately or more than 0.5 mm, approximately or more than 0.2 mm, approximately or more than 0.1mm, approximately or more than 50 ⁇ m, approximately or more than 20 ⁇ m, and approximately or more than 10 ⁇ m.
  • Embodiment 13 The device of Embodiment 1, wherein the biomaterial particles are biocompatible and/or non-toxic.
  • Embodiment 13 wherein the biomaterial particles are biodegradable, and/or the drug molecules are conjugated to the biomaterial particles via ionic or covalent bonding.
  • Embodiment 15 The device of Embodiment 13, wherein the biomaterial particles are stimulus-responsive, optionally wherein the stimulus is selected from the group consisting of pH, temperature, concentrations of cations, concentration of proteins, concentration of small organic molecules, concentrations of nucleic acids, concentrations of other chemicals, ultrasound, and magnetic field.
  • Embodiment 16 Embodiment 16.
  • Embodiment 17 The device of any of Embodiments 1-15, wherein the biomaterial is selected from the group consisting of poly( ⁇ -caprolactone), poly(lactide acid), poly(lactic-co-glycolic acid), poly(acrylic acid), poly(vinyl alcohol, poly(vinylpyrrolidone), poly(ethylene glycol), polyacrylamide, alginate, and dextran.
  • the biomaterial is selected from the group consisting of poly( ⁇ -caprolactone), poly(lactide acid), poly(lactic-co-glycolic acid), poly(acrylic acid), poly(vinyl alcohol, poly(vinylpyrrolidone), poly(ethylene glycol), polyacrylamide, alginate, and dextran.
  • Embodiment 17 The device of any of Embodiments 1-16, wherein at least one biomaterial particle encapsulates exactly one type of active drug molecule.
  • Embodiment 19 The device of any of Embodiments 1-18, wherein the arrangement of the drug molecules within the biomaterial particles is at a uniform density.
  • Embodiment 20 The device of any of Embodiments 1-18, wherein the arrangement of the drug molecules within the biomaterial particles is at a non-uniform density.
  • Embodiment 21 Embodiment 21.
  • Embodiment 20 wherein the arrangement of the drug molecules within the biomaterial particles are at a non-uniform density with higher density near the centroid of the particle as compared to the surface of the particle.
  • Embodiment 22 The device of any of Embodiments 1-21, wherein the cage is constructed from, or comprises, a braid of polymer materials with string-like geometry.
  • Embodiment 23 The device of any of Embodiments 1-21, wherein the cage is constructed from, or comprises, a solid material with pores constructed through cutting and removal of material.
  • Embodiment 24 The device of any of Embodiments 1-23, wherein the cage is enclosed on each extremity with an end cap or weld.
  • Embodiment 25 The device of any of Embodiments 1-24, wherein the device further comprises an anchor for attachment to tissue or organ.
  • Embodiment 26 The device of Embodiment 25, wherein the anchor comprises an endoscopic clip.
  • Embodiment 27 The device of Embodiment 25, wherein the anchor comprises a stent graft.
  • Embodiment 28 The device of Embodiment 25, wherein the anchor comprises a balloon that is mechanically size restricted from passage to the duodenum from the stomach.
  • Embodiment 29 The device of any of Embodiments 26-28, wherein the anchor is connected to the cage via a wire or suture.
  • Embodiment 30 A method for implanting the device of any of Embodiments 1-29, wherein the method comprises: loading the device into the lumen of an endoscope or catheter, navigating the tip of the endoscope to near a disease site, and deploying the device at or near the disease site.
  • Embodiment 31 A method for implanting the device of any of Embodiments 1-29, wherein the method comprises: loading the device over-the-scope to an endoscope, navigating the tip of the endoscope to near a disease site, and deploying the device at or near the disease site.
  • Embodiment 32 Embodiment 32.
  • Embodiment 33 A method for implanting the device of any of Embodiments 1-29, wherein the method comprises: loading the device onto a laparoscopic instrument comprising a set of forceps, navigating the laparoscopic instrument to or near a disease site and deploying the device at or near the disease site.
  • Embodiment 33 A method for implanting the device of any of Embodiments 1-29 wherein the device is attached to the treatment site with a bioabsorbable suture.
  • Embodiment 34 A method for implanting the device of Embodiment 33 wherein the presence and current location of the device within the body can be confirmed by the radiopaque markers.
  • Embodiment 35 Embodiment 35.
  • Embodiment 36 A method for implanting the device of any of Embodiments 1-29, wherein the method comprises: loading the device onto a guidewire, navigating the guidewire via fluoroscopy or ultrasound, and deploying the device at or near a disease site.
  • Embodiment 36 The method of Embodiment 35, wherein the disease site is at or near the heart.
  • Embodiment 37 A method for treating or managing a gastrointestinal disease, the method comprising: implanting the device of any of Embodiments 1-29 into the gastrointestinal tract via an endoscopic clip or suture.
  • Embodiment 38 Embodiment 38.
  • Embodiment 37 wherein the gastrointestinal disease is selected from the group consisting of Crohn’s Disease, ulcerative colitis, pouchitis, toxic megacolon, short segment disease, chemotherapy-derived colitis, microscopic colitis, necrotizing colitis, Celiac disease, and proctitis, and wherein the drug molecules in the device comprise anti-inflammatory drug molecules.
  • Embodiment 39 The method of Embodiment 38, wherein the anti- inflammatory drug molecule is an anti-inflammatory cytokine.
  • Embodiment 40 The method of Embodiment 38, wherein the anti- inflammatory drug molecule is an antagonist for a pro-inflammatory cytokine.
  • Embodiment 41 Embodiment 41.
  • Embodiment 38 wherein the anti- inflammatory drug molecule is a monoclonal antibody.
  • Embodiment 42 The method of Embodiment 37, wherein the gastrointestinal disease is a chronic bacterial infection, and the drug molecules in the device comprise anti- microbial properties.
  • Embodiment 43 The method of Embodiment 42, wherein the chronic bacterial infection is selected from the group consisting of a C. difficile infection, a vancomycin-resistant Enterococcus infection, and an H. pylori infection.
  • Embodiment 44 Embodiment 44.
  • a method for treating or managing infections wherein the infection is selected from the group consisting of a urinary tract infection, and vaginal infection, the method comprising: implanting the device of any of Embodiments 1-29 into the affected site via a catheter.
  • Embodiment 45 The method of Embodiment 44, wherein the drug molecules in the device are selected from the group consisting of anti-microbial peptides, and anti- microbial small molecules.
  • Embodiment 46 The method of Embodiment 37, wherein the gastrointestinal disease is selected from the group consisting of intestinal fistula, peptic ulcer, and Graft vs. Host Disease, and wherein the drug molecules in the device comprise tissue repair drug molecules.
  • Embodiment 47 The method of Embodiment 46, wherein the tissue repair drug molecules comprise a cytokine.
  • Embodiment 48. A drug-eluting device comprising: a porous, topologically closed cage with a maximum pore size of X, one or more biomaterial particles with a minimum diameter greater than Y, wherein at least 50% of the biomaterial particles comprise one or more drug molecules encapsulated within the interior of the particle, and where Y ⁇ X, and wherein one or more drug molecules are formulated into a pharmaceutical composition further comprising one or more strains of bacteria, optionally bacteria are selected from a microbial consortium.
  • Embodiment 48 wherein the maximum pore size X of the closed cage is selected from the group consisting of approximately or less than 1 mm, approximately or less than 0.5 mm, approximately or less than 0.2 mm, approximately or less than 0.1 mm, approximately or less than 50 ⁇ m, approximately or less than 20 ⁇ m, and approximately or less than 10 ⁇ m.
  • Embodiment 50 The device of Embodiment 49, wherein the closed cage has a geometry selected from the group consisting of an approximately cylindrical, approximately spherical, approximately rectangular prism, approximately conical, approximately helical, approximately spiral, and approximately serpentine.
  • Embodiment 51 Embodiment 51.
  • Embodiment 52 The device of any of Embodiments 48-51, wherein the cage material is selected from the group consisting of medical grade stainless steel, cobalt- chromium alloys, platinum, nitinol, and titanium.
  • Embodiment 53 Embodiment 53.
  • Embodiment 54 The device of any of Embodiments 48-51, wherein the cage material comprises medical grade bioabsorbable magnesium.
  • Embodiment 55 The device of any of Embodiments 48-51, wherein the cage material comprises medical grade bioabsorbable magnesium.
  • Embodiment 56 The device of any of Embodiments 48-54, wherein the cage is coated with a material to prevent biofouling, optionally selected from the group consisting of material to prevent biofilm formation, and material to prevent fibrotic foreign body response, such as chelators, anti-virulence compounds, anti-biofilm compounds, N- acetylcysteine, polymer brush coatings, submicron surface textures, and antibiotics.
  • Embodiment 56 The device of any of Embodiments 48-55, wherein the cage is coated with a drug, such as an anti-virulence compound, antibiotic, or biologic.
  • Embodiment 57 The device of any of Embodiments 48-56, wherein the cage comprises a radiopaque component.
  • Embodiment 58 The device of Embodiment 57, wherein the radiopaque component comprises a precious metal selected from the group consisting of gold, platinum, tantalum, and palladium.
  • Embodiment 59 The device of Embodiment 48, wherein the minimum diameter Y of the biomaterial particles is selected from the group consisting of approximately or more than 1 mm, approximately or more than 0.5 mm, approximately or more than 0.2 mm, approximately or more than 0.1mm, approximately or more than 50 ⁇ m, approximately or more than 20 ⁇ m, and approximately or more than 10 ⁇ m.
  • Embodiment 60 The device of Embodiment 48, wherein the biomaterial particles are biocompatible and non-toxic.
  • Embodiment 61 The device of Embodiment 60, wherein the biomaterial particles are biodegradable, and/or the drug molecules are conjugated to the biomaterial particles via ionic or covalent bonding.
  • Embodiment 62 The device of Embodiment 60, wherein the biomaterial particles are stimulus-responsive, optionally wherein the stimulus is selected from the group consisting of pH, temperature, concentrations of cations, the concentration of proteins, the concentration of small organic molecules, concentrations of nucleic acids, concentrations of other chemicals, ultrasound, and magnetic field.
  • Embodiment 63 Embodiment 63.
  • Embodiment 64 The device of any of Embodiments 48-62, wherein the biomaterial is selected from the group consisting of poly( ⁇ -caprolactone), poly(lactide acid), poly(lactic-co-glycolic acid), poly(acrylic acid), poly(vinyl alcohol, poly(vinylpyrrolidone), poly(ethylene glycol), polyacrylamide, alginate, and dextran.
  • Embodiment 64 The device of any of Embodiments 48-63, wherein at least one biomaterial particle encapsulates one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, or nine or more types of active drug molecules.
  • Embodiment 65 Embodiment 65.
  • Embodiment 48-64 The device of any of Embodiments 48-64, wherein the arrangement of the pharmaceutical composition within the biomaterial particles are at a uniform density.
  • Embodiment 66 The device of any of Embodiments 48-64, wherein the arrangement of the pharmaceutical composition within the biomaterial particles are at a non-uniform density.
  • Embodiment 67 The device of Embodiment 66, wherein the arrangement of the pharmaceutical composition within the biomaterial particles are at a non-uniform density with higher density near the centroid of the particle as compared to the surface of the particle.
  • Embodiment 68 The device of any of Embodiments 48-67, wherein the cage is constructed from a braid of polymer materials with string-like geometry.
  • Embodiment 69 The device of any of Embodiments 48-67, wherein the cage is constructed from a solid material with pores constructed through cutting and removal of material.
  • Embodiment 70 The device of any of Embodiments 48-69, wherein the cage is enclosed on each extremity with an end cap or weld.
  • Embodiment 71 The device of any of Embodiments 48-70, wherein the device further comprises an anchor for attachment to tissue.
  • Embodiment 72 The device of Embodiment 71, wherein the anchor comprises an endoscopic clip.
  • Embodiment 73 The device of Embodiment 71, wherein the anchor comprises a stent graft.
  • Embodiment 74 The device of Embodiment 71, wherein the anchor comprises a balloon that is mechanically size restricted from passage to the duodenum from the stomach.
  • Embodiment 75 The device of any of Embodiments 72-74, wherein the anchor is connected to the cage via a wire or suture.
  • Embodiment 76 The device of Embodiment 48, wherein the pharmaceutical composition comprises one strain of bacteria.
  • Embodiment 77 The device of Embodiment 48, wherein the pharmaceutical composition comprises two or more strains of bacteria.
  • Embodiment 78 The device of Embodiment 48, wherein Y > X.
  • Embodiment 79 The device of Embodiment 48, wherein the ratios of one or more strains of bacteria are consistent over time as the bacteria grow.
  • Embodiment 80 The device of any of Embodiments 48-79, wherein at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% of the biomaterial particles comprise the combination of the one or more strains of bacteria encapsulated within the interior of the particles.
  • Embodiment 81 Embodiment 81.
  • a device comprising: a porous, topologically closed cage with a maximum pore size of X, one or more biomaterial particles with a minimum diameter greater than Y, wherein at least 50% of the biomaterial particles comprise a combination of one or more strains of bacteria encapsulated within the interior of the particle, optionally the bacteria are selected from a microbial consortium, and where Y ⁇ X.
  • Embodiment 82 The device of Embodiment 81, wherein each biomaterial particle encapsulates one species of bacteria.
  • Embodiment 83 The device of Embodiment 81, wherein each biomaterial particle encapsulates two or more species of bacteria.
  • Embodiment 84 Embodiment 84.
  • Embodiment 85 The device of Embodiment 81, wherein Y > X.
  • Embodiment 85 The device of Embodiment 81, wherein the ratios of one or more strains of bacteria are consistent over time as the bacteria grow.
  • Embodiment 86 Embodiment 86.
  • the microbial consortium comprises bacteria from one or more genera, species, or strains selected from the group consisting of Faecalibacterium prausnitzii, Limosilactobacillus (which was formerly defined as Lactobacillus), Clostridium XIVa, Clostridium IV, Clostridium leptum, Ruminococcus gnavus, Bifidobacteria, Enterococcaceae spp., Enterobacteriaceae spp., Streptooccaeceae spp., Bacteroides, Bifidobacterium, Roseburia, Suterella, Flavobacterium, Phascaolarctobacterium and Escherichia coli spp, which is also defined as Escherichia coli Nissle 1917.
  • Embodiment 87 The device of any of Embodiments 81-85, wherein at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% of the biomaterial particles comprise the combination of the one or more strains of bacteria encapsulated within the interior of the particles.
  • Embodiment 88 A method for implanting the device of any of Embodiments 48-85, wherein the method comprises: loading the device into the lumen of an endoscope or catheter, navigating the tip of the endoscope to near a disease site, and deploying the device at or near the disease site.
  • Embodiment 89 Embodiment 89.
  • Embodiment 90 A method for implanting the device of any of Embodiments 48-85, wherein the method comprises: loading the device onto a laparoscopic instrument comprising a set of forceps, navigating the laparoscopic instrument near a disease site, and deploying the device at or near the disease site.
  • Embodiment 91 Embodiment 91.
  • Embodiment 92 A method for implanting the device of Embodiment 91 wherein the presence and current location of the device within the body can be confirmed by the radiopaque markers.
  • Embodiment 93 A method for implanting the device of any of Embodiments 48-85, wherein the method comprises: loading the device onto a guidewire, navigating the guidewire via fluoroscopy or ultrasound, and deploying the device at or near the disease site.
  • Embodiment 94 The method of Embodiment 93, wherein the disease site at or near the heart.
  • Embodiment 95 A method for treating or managing a gastrointestinal disease, the method comprising: implanting the device of any of Embodiments 48-79 into the gastrointestinal tract via an endoscopic clip or suture.
  • Embodiment 96 The method of Embodiment 95, wherein the gastrointestinal disease is selected from the group consisting of Crohn’s Disease, ulcerative colitis, pouchitis, toxic megacolon, short segment disease, chemotherapy-derived colitis, microscopic colitis, necrotizing colitis, Celiac disease, and proctitis, and wherein the drug molecules in the device or the bacteria in the device comprise anti-inflammatory properties.
  • Embodiment 97 Embodiment 97.
  • Embodiment 96 wherein the drug molecule is an anti-inflammatory cytokine.
  • Embodiment 98 The method of Embodiment 96, wherein the drug molecule is an antagonist for a pro-inflammatory cytokine.
  • Embodiment 99 The method of Embodiment 96, wherein the drug molecule is a monoclonal antibody.
  • Embodiment 100 The method of Embodiment 95, wherein the gastrointestinal disease is a chronic bacterial infection, and the drug molecules in the device or the bacteria in the device comprise anti-microbial properties.
  • Embodiment 101 Embodiment 101.
  • Embodiment 100 wherein the chronic bacterial infection is selected from the group consisting of a C. difficile infection, a vancomycin-resistant Enterococcus infection, and an H. pylori infection.
  • Embodiment 102 A method for treating or managing infections, wherein the infection is selected from the group consisting of a urinary tract infection, and vaginal infection, the method comprising: implanting the device of any of Embodiments 48-79 into the affected site via a catheter.
  • Embodiment 103 The method of Embodiment 102, wherein the drug molecules in the device are selected from the group consisting of anti-microbial peptides, and anti-microbial small molecules.
  • Embodiment 104 The method of Embodiment 95, wherein the gastrointestinal disease is selected from the group consisting of intestinal fistula, peptic ulcer, and Graft vs. Host Disease, and wherein the drug molecules in the device or the bacteria in the device comprise tissue repair properties.
  • Embodiment 105 The method of Embodiment 104, wherein the drug molecules comprise a cytokine.
  • Embodiment 106 A method for treating or managing a gastrointestinal disease, the method comprising: implanting the device of any of Embodiments 81-85 into the gastrointestinal tract via an endoscopic clip or suture.
  • Embodiment 107 Embodiment 107.
  • Embodiment 106 wherein the gastrointestinal disease is selected from the group consisting of Crohn’s Disease, ulcerative colitis, pouchitis, toxic megacolon, short segment disease, chemotherapy-derived colitis, microscopic colitis, necrotizing colitis, Celiac disease, and proctitis, and wherein the bacteria in the device comprise anti-inflammatory properties.
  • Embodiment 108 The method of Embodiment 106, wherein the gastrointestinal disease is a chronic bacterial infection, and wherein the bacteria in the device comprise anti-microbial properties.
  • Embodiment 109 The method of Embodiment 108, wherein the chronic bacterial infection is selected from the group consisting of a C.
  • Embodiment 110 A method for treating or managing infections, wherein the infection is selected from the group consisting of a urinary tract infection, and vaginal infection, the method comprising: implanting the device of any of Embodiments 81-85 into the affected site via a catheter.
  • Embodiment 111 The method of Embodiment 106, wherein the gastrointestinal disease is selected from the group consisting of intestinal fistula, peptic ulcer, and Graft vs. Host Disease, and wherein the bacteria in the device comprise tissue repair properties.
  • a drug-eluting device comprising a porous, topologically closed cage encompassing one or more biomaterial particles encapsulating one or more therapeutic agents, wherein the device elutes a prophylactically or therapeutically effective amount of one or more drug molecules when implanted at or near a target site in a subject.
  • Embodiment 113 The device of Embodiment 112, wherein one or more therapeutic agents comprise a small molecule and/or a biologic.
  • Embodiment 114 The device of Embodiment 112 or 113, wherein one or more therapeutic agents comprise a microbe or bacterium.
  • Embodiment 115 Embodiment 115.
  • Embodiment 116 An implantable, cell-encapsulation assembly comprising: (a) a device comprising a topologically closed chamber defined by (i) a perforated main body portion and (ii) two end portions, and (b) one or more biomaterial capsules contained in the chamber and encapsulating a first group of cells that, when implanted in host tissue, provide a desired therapeutic or prophylactic effect. [00302] Embodiment 117. The assembly of Embodiment 116, wherein the device further comprises an anchor for attachment to tissue. [00303] Embodiment 118.
  • Embodiment 116 or 117 wherein the perforated main body portion is tubular or substantially tubular.
  • Embodiment 119 The assembly of any of Embodiments 116-118, wherein the two end portions are identical or substantially identical.
  • Embodiment 120 The assembly of any of Embodiments 116-118, wherein the two end portions are different with one end portion further comprising an extension with an elastic coil configuration.
  • Embodiment 121 The assembly of any of Embodiments 116-120, wherein the biomaterial capsules comprise one or more biocompatible polymers.
  • Embodiment 122 Embodiment 122.
  • Embodiment 121 wherein the one or more biocompatible polymers are synthetic polymers.
  • Embodiment 123 The assembly of any of Embodiments 116-122, wherein the first group of cells is a homogenous group of cells.
  • Embodiment 124 The assembly of any of Embodiments 116-122, wherein the first group of cells comprises a microbial consortium comprising a mixture of species.
  • Embodiment 125 The assembly of any of Embodiments 116-124, wherein the first group of cells comprises engineered bacteria expressing one or more desired molecules.
  • Embodiment 126 Embodiment 126.
  • Embodiment 127 An implantable, cell-encapsulation assembly comprising: (a) a device comprising a topologically closed chamber defined by (i) a perforated main body portion and (ii) two end portions, and (b) one or more biomaterial capsules contained in the chamber and encapsulating one or more therapeutic agents. [00313] Embodiment 128.
  • An implantable, cell-encapsulation assembly comprising: (a) a device comprising a topologically closed chamber defined by (i) a perforated main body portion and (ii) two end portions, and (b) one or more biomaterial capsules contained in the chamber and encapsulating one or more microbes (e.g., genetically engineered microbes).
  • a drug-eluting device comprising a porous, topologically closed cage encompassing one or more biomaterial particles encapsulating one or more therapeutic agents, wherein the device elutes a prophylactically or therapeutically effective amount of the one or more therapeutic agents when implanted in, at, or near a target site in a subject.
  • Embodiment 130 The device of Embodiment 129, wherein the one or more therapeutic agents is selected from the group consisting of one or more small molecules, one or more biologics, and a combination thereof.
  • Embodiment 131 The device of Embodiment 129, wherein the one or more therapeutic agents is selected from the group consisting of one or more microbes, one or more bacteria, and a combination thereof.
  • Embodiment 132 The device of Embodiment 131, wherein the one or more microbes or one or more bacteria have been modified to produce or secret one or more small molecules and/or one or more biologics.
  • Embodiment 133 Embodiment 133.
  • An implantable, cell-encapsulation assembly comprising: (a) a device comprising a topologically closed chamber defined by (i) a perforated main body portion and (ii) two end portions, and (b) one or more biomaterial particles contained in the chamber encapsulating a first group of cells that, when implanted in, at, or near a target site in a subject, provide a desired therapeutic or prophylactic effect.
  • Embodiment 134 The assembly of Embodiment 133, wherein the device further comprises an anchor for attachment to tissue in, at, or near the target site.
  • Embodiment 135. The assembly of Embodiment 133 or 134, wherein the perforated main body portion is tubular or substantially tubular.
  • Embodiment 136 The assembly of any of Embodiments 133-135, wherein the two end portions are different with one end portion further comprising an extension with an elastic coil configuration.
  • Embodiment 137 The assembly of any of Embodiments 133-136, wherein the biomaterial particles comprise one or more biocompatible polymers.
  • Embodiment 138 The assembly of Embodiment 137, wherein the one or more biocompatible polymers are synthetic polymers.
  • Embodiment 139 The assembly of any of Embodiments 133-138, wherein the first group of cells comprises a microbial consortium comprising a mixture of two or more bacterial isolates.
  • Embodiment 140 Embodiment 140.
  • Embodiment 141 The assembly of any of Embodiments 133-139, wherein the first group of cells comprises two or more engineered bacterial isolates, each of which expresses one or more desired therapeutic agents which provide the desired therapeutic or prophylactic effect.
  • Embodiment 141 The assembly of any of Embodiments 133-140, wherein the first group of cells sustains for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months after implantation.
  • Embodiment 142 Embodiment 142.
  • a drug-eluting device comprising: a porous, topologically closed cage with a maximum pore size of X, one or more biomaterial particles with a minimum diameter greater than Y, wherein at least 50% of the biomaterial particles comprise one or more therapeutic agents encapsulated within the interior of the particle, and where Y ⁇ X, and wherein the one or more therapeutic agents are formulated into a pharmaceutical composition further comprising one or more strains of bacteria, optionally bacteria are selected from a microbial consortium.
  • a method for implanting the device or the assembly of any of Embodiments 129-142 comprising: loading the device or the assembly into a lumen of an endoscope or catheter, navigating the tip of the endoscope or catheter to in, at, or near the target site, and deploying the device or the assembly in, at, or near the target site.
  • Embodiment 144 A method for implanting the device or the assembly of any of Embodiments 129-142, wherein the method comprises: loading the device or the assembly over-the-scope to an endoscope, navigating the tip of the endoscope to in, at, or near the target site, and deploying the device or the assembly in, at, or near the target site.
  • Embodiment 145 A method for implanting the device or the assembly of any of Embodiments 129-142, wherein the method comprises: loading the device or the assembly onto a laparoscopic instrument comprising a set of forceps, navigating the laparoscopic instrument to in, at, or near the target site, and deploying the device or the assembly in, at, or near the target site.
  • Embodiment 146 A method for implanting the device or the assembly of any of Embodiments 129-142, wherein the device or the assembly is attached in, at, or near the target site with a bioabsorbable suture.
  • Embodiment 147 Embodiment 147.
  • Embodiment 148 A method for implanting the device or the assembly of any of Embodiments 129-142, wherein the method comprises: loading the device or the assembly onto a guidewire, navigating the guidewire via fluoroscopy or ultrasound, and deploying the device or the assembly in, at, or near the target site.
  • Embodiment 148 A method for treating or managing a gastrointestinal disease, the method comprising: implanting the device or the assembly of any of Embodiments 129- 142 in, at, or near the target site via an endoscopic clip or suture, wherein the target site is in a gastrointestinal tract.
  • Embodiment 149 Embodiment 149.
  • Embodiment 148 wherein the gastrointestinal disease is selected from the group consisting of Crohn’s Disease, ulcerative colitis, pouchitis, toxic megacolon, short segment disease, chemotherapy-derived colitis, microscopic colitis, necrotizing colitis, Celiac disease, and proctitis, and wherein the therapeutic agents in the device or the assembly comprise one or more anti-inflammatory drug molecules.
  • Embodiment 150 The method of Embodiment 149, wherein the one or more anti-inflammatory drug molecules comprise an anti-inflammatory cytokine.
  • Embodiment 151 The method of Embodiment 149, wherein the one or more anti-inflammatory drug molecules comprise an antagonist for a pro-inflammatory cytokine.
  • Embodiment 152 The method of Embodiment 149, wherein the one or more anti-inflammatory drug molecules comprise a monoclonal antibody.
  • Embodiment 153 The method of Embodiment 148, wherein the gastrointestinal disease is a chronic bacterial infection, and the therapeutic agents in the device or the assembly comprise anti-microbial properties.
  • Embodiment 154 The method of Embodiment 153, wherein the chronic bacterial infection is selected from the group consisting of a C. difficile infection, a vancomycin-resistant Enterococcus infection, and an H. pylori infection.
  • Embodiment 155 Embodiment 155.
  • a method for treating or managing infections, wherein the infection is selected from the group consisting of a urinary tract infection, and a vaginal infection the method comprising: implanting the device or the assembly of any of Embodiments 129-142 in, at, or near the target site via a catheter.
  • Embodiment 156 The method of Embodiment 155, wherein the therapeutic agents in the device or the assembly are selected from the group consisting of anti- microbial peptides, anti-microbial small molecules, and a combination thereof.
  • Embodiment 157 The method of Embodiment 148, wherein the gastrointestinal disease is selected from the group consisting of intestinal fistula, peptic ulcer, and Graft vs.
  • Embodiment 158 The method of Embodiment 157, wherein the one or more tissue repair drug molecules comprise a cytokine.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Rheumatology (AREA)
  • Dermatology (AREA)
  • Pain & Pain Management (AREA)
  • Medicinal Preparation (AREA)

Abstract

Cette demande concerne un dispositif et un procédé permettant d'administrer localement des médicaments par implantation in vivo au niveau d'un site de maladie. Le dispositif comprend une cage poreuse et topologiquement fermée, une ou plusieurs particules de biomatériau enfermées par la cage, et un ensemble de molécules médicamenteuses encapsulées à l'intérieur des particules. Des molécules médicamenteuses peuvent être éluées à partir des particules de biomatériau, passées à travers les pores de la cage, et transportées vers le site de maladie. Les molécules médicamenteuses peuvent en outre être formulées en une composition pharmaceutique comprenant un consortium microbien de bactéries.
PCT/US2022/042272 2021-09-01 2022-08-31 Dispositif implanté pour libération de médicament à long terme WO2023034460A1 (fr)

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Application Number Priority Date Filing Date Title
US202163239768P 2021-09-01 2021-09-01
US63/239,768 2021-09-01
US202263301876P 2022-01-21 2022-01-21
US63/301,876 2022-01-21

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040143221A1 (en) * 2002-12-27 2004-07-22 Shadduck John H. Biomedical implant for sustained agent release
US8734823B2 (en) * 2005-12-14 2014-05-27 The Invention Science Fund I, Llc Device including altered microorganisms, and methods and systems of use
US9446226B2 (en) * 2005-12-07 2016-09-20 Ramot At Tel-Aviv University Ltd. Drug-delivering composite structures
WO2021026484A1 (fr) * 2019-08-08 2021-02-11 William Marsh Rice University Constructions implantables et leurs utilisations

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040143221A1 (en) * 2002-12-27 2004-07-22 Shadduck John H. Biomedical implant for sustained agent release
US9446226B2 (en) * 2005-12-07 2016-09-20 Ramot At Tel-Aviv University Ltd. Drug-delivering composite structures
US8734823B2 (en) * 2005-12-14 2014-05-27 The Invention Science Fund I, Llc Device including altered microorganisms, and methods and systems of use
WO2021026484A1 (fr) * 2019-08-08 2021-02-11 William Marsh Rice University Constructions implantables et leurs utilisations

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