WO2023196414A1 - Systems and methods for glucose-responsive insulin delivery - Google Patents
Systems and methods for glucose-responsive insulin delivery Download PDFInfo
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- WO2023196414A1 WO2023196414A1 PCT/US2023/017610 US2023017610W WO2023196414A1 WO 2023196414 A1 WO2023196414 A1 WO 2023196414A1 US 2023017610 W US2023017610 W US 2023017610W WO 2023196414 A1 WO2023196414 A1 WO 2023196414A1
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- 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
- A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/02—Prostheses implantable into the body
- A61F2/022—Artificial gland structures using bioreactors
Definitions
- pancreas demonstrate well-functioning pancreatic interactions that play a key role in ensuring glucose homeostasis, with the pancreas producing and releasing hormones (e.g., insulin and glucagon) in response to physiological fluctuations in blood glucose levels (BGLs).
- hormones e.g., insulin and glucagon
- BGLs blood glucose levels
- T1D type 1 diabetes
- the autoimmune destruction of insulin-producing P-cells in the pancreas results in a loss of glycemic control, hi the absence of a cure, reversing insulin deficiency is primarily achieved through the lifelong administration of exogenous insulin via subcutaneous insulin infusions or multiple daily insulin injections.
- insulin replacement therapies have their own limitations, including the risk of hypoglycemia and hyperglycemia from patient-directed excess or insufficient dosing. These limitations continue to pose significant barriers in achieving desirable BGL control with insulin monotherapy. Moreover, ideal diabetes management is contingent upon strict and frequent compliance to psychologically straining caretaking protocols, imposing an enormous burden of self-care on T1D patients. As such, there is an urgent need for (new) technologies and therapies that can mimic dynamic P-cell function by affording desirable glycemic control through continual, autonomous insulin delivery with minimal burden to the patient.
- High mechanical strength and ready permeability to biological molecules are two critical criteria for developing an implantable glucose-responsive insulin delivery device.
- biological molecules e.g. glucose and insulin
- these properties generally do not coexist within the same material and, instead, can even compromise each other.
- elastomers are known to have robust mechanical properties and stability in in vivo environments but suffer from poor permeability.
- hydrogels can have desirable permeability properties but poor mechanical properties and stability when exposed to an in vivo environment.
- PBA phenylboronic acid
- FPBA 4-carboxy-3- fluorophenylboronic acid
- FIG. IB swelling can be reversed under hypoglycemic conditions from a loss of negativenegative charge repulsion, thus mitigating a potential risk of over-dosing on insulin on the return to normoglycemia.
- FIGURE 1A shows a representative scheme of device fabrication to form the hydrogelelastomer hybrid material.
- Hydrogel monomers are dissolved within a precursor elastomer network.
- Crosslinking of the hydrogel network via UV irradiation traps the hydrogel within the elastomer material.
- a final interpenetrating “hybrid” material is formed.
- This hybrid material offers a tunable balance between mechanical strength and permeability towards insulin.
- FIGURE IB shows a representative scheme of glucose-responsive mechanism. Binding of glucose to the hydrogel-elastomer material occurs via the fluorophenylboronic acid (FPBA) monomer incorporated in the hydrogel network.
- FPBA fluorophenylboronic acid
- Binding of glucose and FPBA renders the matrix more hydrophilic while increasing the negative charge density of the system. This increase in negative charge density increases the osmotic pressure in the system, leading to volumetric swelling of the material. The subsequent increase in permeability allows for enclosed insulin to be released.
- FIGURE 2 A shows a representative scheme of the one-pot, dip-coating cannula fabrication procedure.
- FIGURE 2B shows an image of different sized ends-closed cannulas filled with water.
- FIGURE 3A shows an image of a cannula after removal from the fabrication mold (top). The cannula is mechanically robust and can be manually stretched without breakage (bottom).
- FIGURE 3B shows a graph of tensile stress vs tensile strain of the hybrid material as a function of hydrogel concentration (w/v%).
- FIGURE 3C shows a graph of loading- unloading curve of a hydrogel-elastomer sheet made from 12.5% (w/v%) elastomer and 12% (w/v%) hydrogel.
- FIGURE 4A shows a graph of fracture energy of the hybrid material as a function of hydrogel concentration.
- the elastomer (PU-D3) concentration is fixed at 12.5% (w/v%).
- FIGURE 4B shows a graph of ultimate tensile strength of the hybrid material as a function of hydrogel concentration.
- the elastomer (PU-D3) concentration is fixed at 12.5% (w/v%).
- FIGURE 4C shows a graph of Young’s modulus of the hybrid material as a function of hydrogel concentration.
- the elastomer (PU-D3) concentration is fixed at 12.5% (w/v%).
- Data points are means ⁇ SD (n - 3).
- FIGURE 5A shows a graph of BGL-reducing activity of freshly prepared insulin, and insulin extracted from freshly prepared ends-sealed cannulas.
- FIGURE 5C shows a graph of BGL-reducing activity from insulin stored at 4 °C for 4 weeks. Initial BGLs were compared with BGLs at 60 min post injection of the insulin (0.05mg).
- FIGURE 6A shows an image of the hybrid glucose-responsive material membrane.
- Statistical significance was calculated using Two-way ANOVA. * p ⁇ 0.05, ** p ⁇ 0.01, *** p ⁇ 0.001.
- FIGURE 6D shows a graph of the comparison of glucose absorbed by control (PU) and glucose-responsive (FPBA) sheets following Ih exposure to 200 mg/dL of glucose measured via a glucometer (blue) and a GOx assay (red).
- FIGURE 7A shows a graph of the results of in vitro insulin release from ends-closed cannulas made of control (PU) materials in clinically relevant glucose concentrations.
- the glucose concentrations were set at 0, 100, and 400 mg/dL.
- Statistical significance was calculated using Two-way ANOVA, # denotes a statistical difference from 100 mg/mL (p ⁇ 0.05).
- FIGURE 7B shows a graph of the results of in vitro insulin release from ends-closed cannulas made of glucose-responsive (FPBA) materials in clinically relevant glucose concentrations.
- the glucose concentrations were set at 0, 100, and 400 mg/dL.
- FIGURE 7D shows a line graph of in vitro accumulated release of insulin from ends-closed cannulas made of control (PU) materials loaded with 0.750 mg (50 pL of 15 mg/mL) of insulin under different glucose concentrations.
- FIGURE 7E shows a bar graph of in vitro accumulated release of insulin from ends-closed cannulas made of control materials loaded with 0.750 mg (50 pL of 15 mg/mL) of insulin under different glucose concentrations.
- FIGURE 7F shows a graph of pulsatile insulin release from control ends-closed cannulas loaded with 1.5 mg of insulin by alternating the glucose concentration for three consecutive cycles; cannulas were incubated in each solution for 15 min.
- FIGURE 7G shows a line graph of in vitro accumulated release of insulin from ends-closed cannulas made of glucoseresponsive materials loaded with 0.750 mg (50 pL of 15 mg/mL) of insulin under different glucose concentrations.
- FIGURE 71 shows a graph of pulsatile insulin release from glucose-responsive ends-closed cannulas loaded with 1.5 mg of insulin by alternating the glucose concentration for three consecutive cycles; cannulas were incubated in each solution for 15 min.
- FIGURE 8 A shows a representative scheme of the in vivo timeline for ends-closed cannula trial in diabetic mice.
- FIGURE 8B shows a representative image of the method of use of the subcutaneously implanted hybrid-membrane device.
- FIGURE 8D shows a graph of time spent in normoglycemia per treatment group; normoglycemia is defined as BGLs within 100 mg/dL ⁇ x ⁇ 200 mg/dL. Statistical significance between groups was calculated.
- FIGURE 8G shows a graph of blood glucose levels of glucoseresponsive cannula treated mice (FPBA).
- the normoglycemic range is defined as BGLs within 100 mg/dL ⁇ x ⁇ 200 mg/dL.
- FIGURE 9E shows a graph of blood glucose levels of type 1 diabetic mice treated with insulin or insulin loaded PU devices for control and FPBA as glucose-responsive devices. Data points are means +/- SD.
- FIGURE 11A shows an image of ends-closed cannula prior to (left) and immediately after implantation (right) in the subcutaneous space. Mice were shaved and prior to implantation.
- FIGURE 11B shows an image of H&E (top) and Masson Trichrome (bottom) staining of a retrieved ends-sealed cannula one week after subcutaneous implantation.
- FIGURE 11C shows images of ends-sealed cannula prior to implantation (right) and during retrieval (left) after one- week implantation. After a minor incision, the cannulas can be retrieved completely without tissue adhesion or major deformation.
- FIGURE 12 shows images of H&E staining of ends-sealed cannula post-retrieval at one week from the subcutaneous space of C57BL/6 diabetic mice.
- An image of the longitudinal section of the cannula is shown (center), and some images from the cannula-host boundary are shown in the surrounding magnified images.
- the asterisk (*) indicates the host side of the device-host boundary.
- FIGURE 13 A shows images of H&E staining of ends-sealed cannula one week from the subcutaneous space of C57BL/6 mice, emphasizing the initial cell adhesion response at the lowest magnitude. Arrows indicate cell attachment; the asterisk (*) indicates the host side of the devicehost boundary.
- FIGURE 13B shows images of H&E staining of ends-sealed cannula one week from the subcutaneous space of C57BL/6 mice, emphasizing the initial cell adhesion response at a magnitude between the lowest and highest selected magnitudes. Arrows indicate cell attachment; the asterisk (*) indicates the host side of the device-host boundary.
- FIGURE 13C shows images of H&E staining of ends-sealed cannula one week from the subcutaneous space of C57BL/6 mice, emphasizing the initial cell adhesion response at the highest magnitude. Arrows indicate cell attachment; the asterisk (*) indicates the host side of the device-host boundary.
- FIGURE 14A shows a representative scheme of the core-shell cannula is designed such that it contains an open inner lumen (left) and a sealed, glucose-responsive membrane that is wrapped around the inner lumen.
- FIGURE 14B shows a representative scheme of the open inner lumen (left) is connected to an external bolus port on the insulin reservoir via a silicone tube, allowing for rapid infusions of large quantities of insulin. Basal insulin delivery (right) is supported by the glucose-responsive membrane. To prevent leaking, the distal end of the glucose-responsive membrane is sealed shut onto the open inner lumen. The proximal end is left open to the insulin reservoir, allowing for diffusion of insulin to the cannula.
- FIGURE 14C shows a representative image of the core-shell cannula attached to the bottom of the insulin reservoir.
- the glucose-responsive membrane (clear) is conical to maximize volume for insulin diffusion while enabling insertion via an introducing needle.
- FIGURE 14D shows a representative image of compiled device, with silicone tubing extending outwards of insulin reservoir to demonstrate the bolus infusion port. Ruler units in all images are in cm.
- FIGURE 14E shows a representative top and bottom images of the dual-port reservoir prior to closing. Ruler units in all images are in cm.
- FIGURE 14F shows a representative top and bottom images of the dual-port reservoir after closing. Ruler units in all images are in cm.
- FIGURE 14G shows a representative image of a 27ga needle through the inner lumen of an elongated core-shell cannula prototype to demonstrate needle-guided insertion.
- FIGURE 15 shows a representative images to qualitatively monitor diffusion from the core- shell cannula.
- the device was inserted into an alginate/acrylamide tough hydrogel skin mimic (left). Over time, the dye can be seen permeating along the entire length of the cannula, indicating that the entire shell of the cannula is permeable.
- FIGURE 16D shows a graph of BGL-reducing activity of freshly prepared insulin, insulin extracted from freshly prepared core-shell cannulas, and from insulin stored in insulin reservoirs of core-shell cannulas for 1 week at room temperature in diabetic mice.
- FIGURE 17C shows a graph of basal insulin release rate distribution by age from insulin pump users. Graph reproduced from TTDEPOOL.
- FIGURE 18B shows a line graph of in vitro accumulated release of insulin from cylindrical core-shell cannula devices made glucose-responsive materials loaded with 200 pL of U100 insulin (3.47 mg/mL) under different glucose concentrations.
- FIGURE 19 shows a graph of in vitro insulin accumulated from 2U bolus insulin injection through core-shell device compared to a direct injection into the collection buffer.
- FIGURE 20A shows graphs of ultimate tensile stress (MPa), tensile strain (mm/mm), and Young’s modulus (MPa) of the elastomer as a function of concentration in the precursor solution (w/v%).
- MPa ultimate tensile stress
- mm/mm tensile strain
- MPa Young’s modulus
- FIGURE 20B shows graphs of ultimate tensile stress (MPa), tensile strain (mm/mm), and Young’s modulus (MPa) of the elastomer as a function of concentration in the precursor solution (w/v%).
- MPa ultimate tensile stress
- mm/mm tensile strain
- MPa Young’s modulus
- FIGURE 22A shows a graph of effects of insulin concentration on in vitro insulin release rates.
- Insulin release from ends-sealed control cannulas (PU) loaded with ⁇ 50pL of 25 mg/mL of insulin.
- FIGURE 22B shows a graph of effects of insulin concentration on in vitro insulin release rates.
- FIGURE 22C shows a graph of effects of insulin concentration on in vitro insulin release rates.
- FIGURE 22D shows a graph of effects of insulin concentration on in vitro insulin release rates.
- Insulin release from ends- sealed glucose-responsive cannulas loaded with ⁇ 50pL of 25 mg/mL of insulin (top) and with ⁇ 50pL of 10 mg/mL of insulin (bottom).
- FIGURE 23 A shows representative schematic illustration of the method of action of the externally refillable, transcutaneous cannula.
- the mouse VABTM transcutaneous button has a 22ga connector through which the glucose-responsive cannula can be attached to via a silicone adapter.
- the external adapter can then be used for quick, aseptic filling and refilling of insulin of the implanted cannula via a syringe.
- the cannula can then moderate insulin release in a glucoseresponsive fashion.
- FIGURE 23B shows a representative schematic illustration of timeline for transcutaneous, externally refillable cannula trial in diabetic mice.
- FIGURE 23D shows a graph of individual BGL curves for mice with the transcutaneous cannula; black arrows indicate when a fresh infusion of insulin (0.375 mg); red arrow indicates when insulin was removed from the cannula.
- Grey area represents the normoglycemic range as defined by BGLs within 100 mg/dL ⁇ x ⁇ 200 mg/dL.
- FIGURE 23E shows a graph of individual BGL curves for subcutaneous injections of insulin; black arrows indicate when a fresh subcutaneous injection of insulin (0.05mg) was administered.
- Grey area represents the normoglycemic range as defined by BGLs within 100 mg/dL ⁇ x ⁇ 200 mg/dL.
- FIGURE 24A shows a representative schematic illustration of the externally refillable, transcutaneous cannula by attaching a one-end sealed cannula to a commercially available mouse VABTM button (INSTECH) (1) to externally refill (2) the implanted cannula using the aseptic, external filling port.
- FIGURE 24B shows images of top-down view of completed device where the cannula is filled with blue-dyed water to demonstrate a filled cannula (top), and the underside of the device (bottom). The cannula is connected to the mouse VABTM button (INSTECH) via a silicone tube that is glued onto the cannula.
- FIGURE 24C shows images of the device before (left) and after (middle) implantation. The red cap (right) is used to close the refilling port and protect the button when group housing mice.
- FIGURE 24D shows images of the device prior to (top) and after (bottom) refilling.
- FIGURE 25 shows a representative image of an insulin delivery ring prototype (left) in comparison to a commercially available intravaginal ring used for birth control purposes (NuvaRing®).
- the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”) or “containing” (and any form of containing, such as “contains” and “contain”) are inclusive or open- ended and do not exclude additional, unrecited elements or method steps.
- treating includes alleviation of the symptoms associated with a specific disorder or condition and/or preventing or eliminating said symptoms.
- the terms “effective amount” or “therapeutically effective amount” of a compound refers to a nontoxic but sufficient amount of the compound to provide the desired effect.
- the amount that is “effective” will vary from subject to subject, depending on the age and general condition of the individual, mode of administration, and the like. Thus, it is not always possible to specify an exact “effective amount.” However, an appropriate “effective” amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.
- % and wt. % will equally mean % by weight of the total weight.
- subject means an animal including but not limited to, humans, domesticated animals including horses, dogs, cats, cattle, and the like, rodents, reptiles, and amphibians
- patient means an animal including but not limited to, humans, domesticated animals including horses, dogs, cats, cattle, and the like, rodents, reptiles, and amphibians being administered a therapeutic treatment either with or without physician oversight.
- patient means an animal including but not limited to, humans, domesticated animals including horses, dogs, cats, cattle, and the like, rodents, reptiles, and amphibians being administered a therapeutic treatment either with or without physician oversight.
- a device comprising i) one or more hydrogel components and ii) an elastomer.
- the glucose binding composition comprises phenylboronic acid (PBA), or wherein the glucose binding composition comprises 4-carboxy-3-fluorophenylboronic acid (FPBA), or wherein the glucose binding composition comprises PBA and FPBA.
- PBA phenylboronic acid
- FPBA 4-carboxy-3-fluorophenylboronic acid
- the glucose binding composition comprises PBA and FPBA.
- the glucose binding composition consists essentially of PBA, or wherein the glucose binding composition consists essentially of FPBA, or wherein the glucose binding composition consists essentially of PBA and FPBA.
- the device of clause 2 any other suitable clause, or any combination of suitable clauses, wherein the glucose binding composition consists of PBA, or wherein the glucose binding composition consists of FPBA, or wherein the glucose binding composition consists of PBA and FPBA.
- MBAA N’-methylenebis(acrylamide)
- the device of clause 1, any other suitable clause, or any combination of suitable clauses, wherein the one or more hydrogel components comprise a photo initiator.
- the elastomer is a polyurethane.
- the polyurethane comprises a HydroMed D3 polyurethane.
- the polyurethane consists essentially of a HydroMed D3 polyurethane.
- the polyurethane consists of a HydroMed D3 polyurethane.
- any other suitable clause, or any combination of suitable clauses wherein the polyurethane is selected from the group consisting of a HydroMed D7, D4, D3, DI, D6, D640 polyurethane, and combinations thereof.
- the elastomer solution comprises a concentration of 16-20 wt%.
- the device of clause 51, any other suitable clause, or any combination of suitable clauses, wherein the implantable device is removable.
- a process for producing a device comprising the steps of: a) combining one or more hydrogel components and a liquid composition comprising an elastomer to form a liquid combination, b) evaporating the liquid combination to form a hydrogel matrix, c) irradiating the hydrogel matrix to form the device.
- step b) is performed on the liquid combination in the mold.
- step c) is performed on the hydrogel matrix in the mold.
- step d) comprises removing the device from the mold.
- step 74, any other suitable clause, or any combination of suitable clauses, wherein step d) comprises placing the device in water.
- PBA phenylboronic acid
- FPBA 4-carboxy-3 -fluoro phenylboronic acid
- the glucose binding composition comprises PBA and FPBA.
- a device comprises i) one or more hydrogel components and ii) an elastomer.
- the one or more hydrogel components comprise a glucose binding composition.
- the glucose binding composition comprises phenylboronic acid (PBA).
- PBA phenylboronic acid
- FPBA 4-carboxy-3-fluorophenylboronic acid
- the glucose binding composition consists essentially of FPBA.
- the glucose binding composition consists of FPBA.
- the one or more hydrogel components comprise a crosslinker.
- the crosslinker comprises N, N’-methylenebis(acrylamide) (MBAA).
- the crosslinker consists essentially of MBAA.
- the crosslinker consists of MBAA.
- the one or more hydrogel components comprise a photo initiator.
- the photo initiator comprises Irgacure 2959 (IR2959).
- the photo initiator consists essentially of IR2959.
- the photo initiator consists of IR2959.
- the elastomer is a polyurethane.
- the polyurethane comprises a HydroMed D3 polyurethane.
- the polyurethane consists essentially of a HydroMed D3 polyurethane.
- the polyurethane consists of a HydroMed D3 polyurethane.
- the polyurethane is selected from the group consisting of a HydroMed D7, D4, D3, DI, D6, D640 polyurethane, and combinations thereof.
- the elastomer is a product of an elastomer solution.
- the elastomer solution comprises a concentration of 18 wt%.
- the elastomer solution comprises a concentration of 16-20 wt%.
- the elastomer forms an elastomeric network.
- the hydrogel components form a hydrogel.
- the hydrogel is photocrosslinked.
- the hydrogel is contained in an elastomeric network.
- the hydrogel-elastomeric network forms an interpenetrating network.
- the interpenetrating network is configured to release insulin.
- the insulin can be released from any portion of the interpenetrating network.
- the insulin can be released from one or more non-perforated portions of the interpenetrating network.
- the device further comprises insulin.
- the insulin is a fast acting insulin.
- fast acting insulin refers to insulin analogues and/or insulin derivatives, wherein the insulin-mediated effect begins within 5 to 15 minutes and continues to be active for 3 to 4 hours.
- fast acting insulins include, but are not limited to, the following: (i). insulin aspart; (ii). insulin lispro and (iii). insulin glulisine.
- the insulin is a long acting insulin.
- the insulin comprises a fast acting insulin, a long acting insulin, or a combination thereof.
- long acting insulin refers to insulin analogues and/or insulin derivatives, wherein the insulin-mediated effect begins within 0.5 to 2 hours and continues to be active for about or more than 24 hours.
- long acting insulins include, but are not limited to, the following: (i). insulin glargine; (ii). insulin detemir and (iii). insulin degludec.
- the device is irradiated.
- the irradiation is ultraviolet irradiation.
- the device is configured to comprise a therapeutic agent.
- the therapeutic agent is insulin.
- the insulin is a fast acting insulin.
- the insulin is a long acting insulin.
- the insulin comprises a fast acting insulin, a long acting insulin, or a combination thereof.
- the device is configured to contain a surfactant.
- the surfactant is a non-ionic surfactant.
- the surfactant comprises n-Octyl-[3-d- glucoside.
- the surfactant consists essentially of n-Octyl- ⁇ -d-glucoside.
- the surfactant consists of n-Octyl- ⁇ -d-glucoside.
- the device is configured to absorb glucose.
- the device is a permeable device for the absorption of glucose.
- the absorption occurs in a glucose responsive manner.
- the absorption occurs under hypoglycemic conditions.
- the absorption occurs under hyperglycemic conditions.
- the device is implantable.
- the implantable device is removable.
- the device does not comprise a glucose-responsive plug. In an embodiment, the device is substantially free of electronics. [0059] In an embodiment, the device is a tube. In an embodiment, the tube is sealed with a thermoseal. In an embodiment, the tube is sealed at a first end of the tube, at a second end of the tube, or both. In an embodiment, the first end of the tube is sealed with a thermoseal. In an embodiment, the second end of the tube is sealed with a thermoseal. In an embodiment, the first end of the tube is sealed with a thermoseal and the second end of the tube is sealed with a thermoseal.
- the device is a cannula. In an embodiment, the device is a ring-shaped device. In an embodiment, the device is an intravaginal delivery device.
- a process for producing a device comprises the steps of: a) combining one or more hydrogel components and a liquid composition comprising an elastomer to form a liquid combination, b) evaporating the liquid combination to form a hydrogel matrix, and c) irradiating the hydrogel matrix to form the device.
- the process is performed via a one-pot system.
- a “one- pot” system can refer to a facile and efficient strategy for constructing a device compared to traditional stepwise methods and modifications for creation of devices.
- the device is an interpenetrating network.
- the liquid composition comprising an elastomer is a solution.
- the elastomer solution comprises a concentration of 18 wt%.
- the elastomer solution comprises a concentration of 16-20 wt%.
- the process comprises use of a mold to form the device.
- the liquid combination of step a) is placed in the mold.
- step b) is performed on the liquid combination in the mold.
- step c) is performed on the hydrogel matrix in the mold.
- the process further comprises a step d), wherein step d) comprises removing the device from the mold. In an embodiment, step d) comprises placing the device in water.
- the irradiation is ultraviolet irradiation.
- the hydrogel matrix is photocrosslinked.
- the process further comprises a step of adding insulin to the device.
- the insulin is a fast acting insulin.
- the insulin is a long acting insulin.
- the insulin comprises a fast acting insulin, a long acting insulin, or a combination thereof.
- the process further comprises a step of adding a surfactant to the device.
- the surfactant is a non-ionic surfactant.
- the surfactant comprises n-Octyl- ⁇ -d-glucoside.
- the surfactant consists essentially of n- Octyl-P-d-glucoside.
- the surfactant consists of n-Octyl- ⁇ -d-glucoside.
- the one or more hydrogel components comprise a glucose binding composition.
- the glucose binding composition comprises phenylboronic acid (PBA).
- PBA phenylboronic acid
- FPBA 4-carboxy-3-fluorophenylboronic acid
- the glucose binding composition consists essentially of FPBA.
- the glucose binding composition consists of FPBA.
- the one or more hydrogel components comprise a crosslinker.
- the crosslinker comprises N, N’-methylenebis(acrylamide) (MBAA).
- MBAA N, N’-methylenebis(acrylamide)
- the crosslinker consists essentially of MBAA. In an embodiment, the crosslinker consists of MBAA.
- the one or more hydrogel components comprise a photo initiator.
- the photo initiator comprises Irgacure 2959 (IR2959).
- the photo initiator consists essentially of IR2959.
- the photo initiator consists of IR2959.
- the elastomer is a polyurethane.
- the polyurethane comprises a HydroMed D3 polyurethane.
- the polyurethane consists essentially of a HydroMed D3 polyurethane.
- the polyurethane consists of a HydroMed D3 polyurethane.
- the polyurethane is selected from the group consisting of a HydroMed D7, D4, D3, DI, D6, D640 polyurethane, and combinations thereof.
- the elastomer forms an elastomeric network.
- the device is configured to absorb glucose.
- the device is a permeable device for the absorption of glucose.
- the absorption occurs in a glucose responsive manner.
- the absorption occurs under hypoglycemic conditions.
- the absorption occurs under hyperglycemic conditions.
- the device is implantable. In an embodiment, the implantable device is removable.
- the device does not comprise a glucose-responsive plug. In an embodiment, the device is substantially free of electronics.
- the device is a tube.
- the tube is sealed with a thermoseal.
- the tube is sealed at a first end of the tube, at a second end of the tube, or both.
- the first end of the tube is sealed with a thermoseal.
- the second end of the tube is sealed with a thermoseal.
- the first end of the tube is sealed with a thermoseal and the second end of the tube is sealed with a thermoseal.
- the device is a cannula. In an embodiment, the device is a ring-shaped device. Tn an embodiment, the device is an intravaginal delivery device.
- a method of treating a disease in a subject using the device as described herein comprises the step of administering insulin to the subject via the device.
- the device is implanted in the subject. In an embodiment, the device is subsequently removed from the subject.
- the disease is a glucose-responsive disease.
- the disease is diabetes.
- the diabetes is Type 1 diabetes.
- the diabetes is Type 2 diabetes.
- the device is a tube. In an embodiment, the device is a cannula. In an embodiment, the device is a ring-shaped device. In an embodiment, the device is an intravaginal delivery device.
- kits comprises i) one or more hydrogel components, ii) an elastomer, and iii) instructions for producing a device.
- the one or more hydrogel components comprise a glucose binding composition.
- the glucose binding composition comprises phenylboronic acid (PBA).
- PBA phenylboronic acid
- FPBA 4-carboxy-3-fluorophenylboronic acid
- the glucose binding composition consists essentially of FPBA.
- the glucose binding composition consists of FPBA.
- the one or more hydrogel components comprise a crosslinker.
- the crosslinker comprises N, N’-methylenebis(acrylamide) (MBAA).
- MBAA N, N’-methylenebis(acrylamide)
- the crosslinker consists essentially of MBAA. In an embodiment, the crosslinker consists of MBAA.
- the one or more hydrogel components comprise a photo initiator.
- the photo initiator comprises Irgacure 2959 (IR2959).
- the photo initiator consists essentially of IR2959.
- the photo initiator consists of IR2959.
- the elastomer is a polyurethane.
- the polyurethane comprises a HydroMed D3 polyurethane.
- the polyurethane consists essentially of a HydroMed D3 polyurethane.
- the polyurethane consists of a HydroMed D3 polyurethane.
- the polyurethane is selected from the group consisting of a HydroMed D7, D4, D3, DI, D6, D640 polyurethane, and combinations thereof.
- the elastomer is a product of an elastomer solution.
- the elastomer solution comprises a concentration of 18 wt%.
- the elastomer solution comprises a concentration of 16-20 wt%.
- the elastomer forms an elastomeric network.
- the hydrogel components form a hydrogel.
- the hydrogel is photocrosslinked.
- the hydrogel is contained in an elastomeric network.
- the hydrogel-elastomeric network forms an interpenetrating network.
- the interpenetrating network is configured to release insulin.
- the insulin can be released from any portion of the interpenetrating network.
- the insulin can be released from one or more non-perforated portions of the interpenetrating network.
- the device further comprises insulin.
- the insulin is a fast acting insulin.
- the insulin is a long acting insulin.
- the insulin comprises a fast acting insulin, a long acting insulin, or a combination thereof.
- the device is irradiated. In an embodiment, the irradiation is ultraviolet irradiation. [0093] In an embodiment, the device is configured to comprise a therapeutic agent. In an embodiment, the therapeutic agent is insulin. In an embodiment, the insulin is a fast acting insulin. In an embodiment, the insulin is a long acting insulin. In an embodiment, the insulin comprises a fast acting insulin, a long acting insulin, or a combination thereof.
- the device is configured to contain a surfactant.
- the surfactant is a non-ionic surfactant.
- the surfactant comprises n-Octyl-
- the surfactant consists essentially of n-Octyl- ⁇ -d-glucoside.
- the surfactant consists of n-Octyl- ⁇ -d-glucoside.
- the device is configured to absorb glucose.
- the device is a permeable device for the absorption of glucose.
- the absorption occurs in a glucose responsive manner.
- the absorption occurs under hypoglycemic conditions.
- the absorption occurs under hyperglycemic conditions.
- the device is implantable.
- the implantable device is removable.
- the device does not comprise a glucose-responsive plug. In an embodiment, the device is substantially free of electronics.
- the device is a tube.
- the tube is sealed with a thermoseal.
- the tube is sealed at a first end of the tube, at a second end of the tube, or both.
- the first end of the tube is sealed with a thermoseal.
- the second end of the tube is sealed with a thermoseal.
- the first end of the tube is sealed with a thermoseal and the second end of the tube is sealed with a thermoseal.
- the device is a cannula. In an embodiment, the device is a ring-shaped device. In an embodiment, the device is an intravaginal delivery device.
- FPBA 4-2-acrylamidoethy1carbamoyl-3-fluorophenyl boronic acid
- AEC-FPBA 4-2-acrylamidoethy1carbamoyl-3-fluorophenyl boronic acid
- AECPBA 4-aminoethylcarbamoyl-3-fluorophenylboronic acid
- a commercially available polyurethane (PU, HydroMed D3) was dissolved in a 95:5 mixture of ethanol (EtOH) and Mili-Q water to obtain an 18 w/v% solution.
- Films and tubes were prepared using a solution-casting method at room temperature ( Figure 2A). After evaporation of the solvent mixture, molds were immersed in water, allowing the material to crosslink, swell, and release from the molds. The prepared tubes or films were then stored in water for a subsequent three days, with water changed daily. Rather than fully cylindrical cannulas, conical molds were selected to minimize resistance during the needle-assisted insertion process of the core-shell cannulas.
- UV- polymerization of the hydrogel material was triggered using an Omnicare UV for 300 seconds. After UV treatment, the elastomer-hydrogel thin films/tubes were immersed in DI water for three days to ensure full swelling and crosslinking of the elastomer material. Unreacted monomers were removed through daily water changes.
- Insulin was prepared according to a previously described protocol. Briefly, insulin (25 mg) and n-octyl-glucopyranoside (3.65 mg) were dissolved in 0.1 M NaOH aqueous solution (600 pL). 4-(2-hydroxyethyl)-l -piperazineethanesulfonic acid) (HEPES) (12.6 mg) was then added, and the volume was brought to 1 mL by a slow addition of 0.1 M HCL. A transparent solution was obtained at ⁇ pH 7.
- HEPES 4-(2-hydroxyethyl)-l -piperazineethanesulfonic acid
- Cannulas were formed using a solvent casting method. Ends-sealed cannulas were thermosealed on one end, filled with insulin, and thermo- sealed on the filling end to create a closed device. Transcutaneous, externally refillable cannulas were formed by adding a silicone tube (SMI Silicone Tubing Tube 0.025” X 0.047” 50D CL) to an open end of the solvent-casted cannula. The silicone tube was secured in place with the addition of UV glue. The other end of the cannula (not attached to the silicone tube) was then sealed via thermo-sealing. Then, the silicone-end of the cannula was slipped on to the 22-gauge adapter of the mouse VABTM button (INSTECH), creating the final, ready-to-use product.
- INSTECH mouse VABTM button
- 3D CAD models of the insulin reservoirs were designed using 3D modeling software (Autodesk 3ds Max). The reservoirs were printed on a 3D printer (Form 2, Formlabs), using clear resin material (Formlabs). Samples were washed in 2-propanol for 15 minutes, and cured under UV at 60°C for 60 min.
- Core-shell cannulas were fabricated as follows. A silicone tube (SMI Silicone Tubing 0.025” X 0.047” 50 D CL) was then fitted inside the lumen of the glucose-responsive and control cannulas. The two layers of the cannula were glued together (UV glue, J-B Weld) at the distal end of the cannula to create a sealed outer lumen. The combined, core-shell cannula was then fitted to the bottom opening of the insulin reservoir and sealed in place with UV glue. The rest of the openings on the insulin reservoir were sealed with PDMS to create a rubber stopper to keep contents inside the reservoir aseptic while allowing for refilling of the reservoir via needle insertion.
- a silicone tube SMI Silicone Tubing 0.025” X 0.047” 50 D CL
- the two layers of the cannula were glued together (UV glue, J-B Weld) at the distal end of the cannula to create a sealed outer lumen.
- mice Male C57BL/6J mice; 8 weeks old; The Jackson Laboratory.
- STZ streptozotocin
- mice were intraperitoneally injected with STZ (140 mg/kg). After 1 week, mice with a fasting blood glucose level higher than 300 mg/dL were confirmed as type 1 diabetic mice and used for further experiments.
- the stability of insulin in the devices was evaluated using a blood glucose reduction protocol. Devices were first prepared as described above and stored under static conditions at either 4°C or 37°C to evaluate long term storage and in vivo temperature effects of the enclosed insulin, respectively. At pre-determined time points, insulin from the devices was extracted and subsequently subcutaneously injected into diabetic mice at a set dose of 0.05 mg. The blood glucose of the mice (as measured with a Clarity GL2Plus glucose meter) was monitored prior-to and one hour after the insulin injection. The reduction in BGL was attributed to the physiological action of the injected insulin.
- a freshly prepared device indicates a device that was made and immediately had the insulin extracted after thermo- sealing; a freshly made device was used to evaluate the effects of the fabrication procedure on the therapeutic potential of insulin.
- the BGL reduction of a freshly prepared insulin solution (or native insulin solution) was used as control.
- Membranes (1cm x 1cm x 0.5 cm) were placed in glass vials with 10 mL phosphate buffer saline (PBS, pH 7.4) containing different glucose concentrations (100, 200, or 400 mg/dL). The vials were incubated at room temperature, and the glucose concentration of the supernatant was monitored at timed intervals using a glucose meter (Clarity BG 1000, CD-BG1). The concentration of the solution was calculated using an established standard curve.
- PBS phosphate buffer saline
- Glucose absorption was determined following the outlined protocol for the Glucose Oxidase (GO) Kit (Sigma- Aldrich, catalog no. GAGO20). Briefly, membranes (1cm x 1cm x 0.5 cm) were placed in glass vials containing 10 mL PBS (pH 7.4) and different glucose concentrations (100, 200, or 400 mg/dL). The vials were incubated at room temperature. At timed intervals, a 1 mL supernatant solution from each sample was collected and pipetted into a test tube. Assay Reagent (2mL, GO kit) was added to the collected supernatant, an incubated at 37°C for 30 minutes.
- Assay Reagent 2mL, GO kit
- the reaction was stopped after 30 minutes by the addition of 2 mL of 6M H2SO4.
- the absorbance of each sample was measured at 540 nm using UV/Vis spectrophotometry (Beckman Coulter DU 730).
- the concentration of the solution was calculated using an established standard curve.
- Insulin release was determined as a function of glucose concentration over time.
- Devices loaded with insulin (1.25 mg) were placed in centrifuge tubes containing the release medium (2 mL of PBS, pH 7.4) at different concentrations of glucose (0, 100, or 400 mg/dL).
- Samples were thermo-sealed and incubated at 37°C, 70 revolutions per minute (RPM) for the duration of the experiment.
- RPM revolutions per minute
- a clear supernatant 50 pL
- 50 pL was collected and added to Coomassie blue (300 pL); 50 pL of fresh release medium was added to each centrifuge tube following collection of the supernatant.
- Absorbance of the solution was measured at 595 nm, with the concentration calibrated using an established standard curve.
- the glucose-responsiveness of the devices (R) was calculated as the ratio of insulin release under hyperglycemic glucose (400 mg/dL) to normal glucose (100 mg/dL).
- Diabetic mice were allocated to different groups and were treated with subcutaneously injected native insulin or with implanted devices containing 1.5 mg of human recombinant insulin (100 pL of a 15 mg/mL solution).
- FPBA devices were used as test groups, and PU devices were used as control devices.
- the BGLs were monitored using a Clarity GL2Plus glucose meter.
- the intraperitoneal glucose tolerance test was performed to confirm the in vivo glucose-responsive nature of the implanted devices. Prior to the experiment, mice were fasted overnight and then allocated to different groups and treated with subcutaneously implanted devices (e.g. FPBA or PU devices). Once normoglycemia (BGL: 100 mg/dL ⁇ x 200 mg/dL) was achieved approximately 1 hour after device implantation, a glucose solution was injected intraperitoneally into all mice at a dose of 1.5 g/kg. Glucose levels were then monitored at specific time points to assess the return to normoglycemia following the glucose injection. The IPGTT was performed on healthy, non-diabetic mice as control.
- IPGTT intraperitoneal glucose tolerance test
- mice To measure the serum insulin concentration of the mice, 50
- ALPCO Human Insulin ELISA kit
- Hydrogels have been extensively explored for precise drug delivery purposes given their ability to respond to a stimulus (e.g., glucose) via physiological changes to their network to release enclosed cargo (e.g., insulin).
- a stimulus e.g., glucose
- enclosed cargo e.g., insulin
- Several different hydrogel materials functionalized with glucose responsive moieties have been successfully shown to mitigate hyperglycemia through stimuli- responsive insulin release.
- clinical translation remains poor, as many hydrogels suffer from weak mechanical properties, which are further exacerbated by the harsh in vivo milieu. This raises significant concerns in the case of device failure or medical complications, as complete retrieval of hydrogel devices after implantation becomes nearly impossible if the hydrogel matrix has been compromised. Not to mention that retrievability is a crucial factor associated with the regulatory approval processes.
- a one-pot solvent exchange method to produce an elastomer-hydrogel interpenetrating network material with robust mechanical properties capable of forming implantable devices is provided ( Figures 1A, IB, 2A).
- the fabrication process begins by incorporating and dissolving the hydrogel network components — a glucose binding moiety (FPBA), crosslinker (MBAA), and photo-initiator (IR2959) — to a pre-prepared elastomer (PU-D3) solution. Then, a solvent-casting method is employed in which a mold is selected for the hybrid material to obtain the final desired geometry and shape of the implantable device ( Figure 2A). The solvent is then evaporated at ambient temperature before UV treatment using an Omicare UV.
- FPBA glucose binding moiety
- MBAA crosslinker
- IR2959 photo-initiator
- the hydrogel matrix Under UV irradiation, the hydrogel matrix is photo-crosslinked to entrap the hydrogel within the elastomer network, thereby forming an interpenetrating network material (Figure 1A). After immersing the cross-linked material in water, the hybrid material swells off from the fabrication mold, producing a uniform and ready-to-use final cannula (Figure 2A).
- the hybrid material responds to changes in glucose concentrations rapidly due to the incorporation of FPBA or PBA (see, e.g., Figure IB).
- glucose can reversibility and dynamically bind to phenylboronic acids, rendering the phenylboronic acid more hydrophilic while increasing the negative charge density of the system.
- This increase in hydrophilic character increases the permeability of the carrier material to release insulin in a glucose-responsive fashion. Without being bound by any theory, the process is demonstrated as reversible, with insulin release “turned-off’ under hypoglycemic conditions.
- the potential of the hybrid material to serve as a glucose-responsive insulin delivery device is evaluated.
- the devices can be loaded with insulin to form an insulin delivery device.
- the device responds to changes in glucose concentrations rapidly due to the incorporation of phenylboronic acid (PBA).
- PBA phenylboronic acid
- glucose can reversibility and dynamically bind to phenylboronic acids, rendering the phenylboronic acid more hydrophilic while increasing the negative charge density of the system.
- This increase in hydrophilic character increases the permeability of the carrier material, to release insulin in a glucose-responsive fashion (Figure IB). The process is reversible, with insulin release shut off under hypoglycemic conditions.
- Prepared tubes may be thermo-sealed at one end, subsequently loaded with an insulin solution, followed by thermo-sealing of the filling end to create a closed device.
- the simple fabrication process is conducive to scale-up or scale-down requirements, as the final form of the device is contingent upon the mold selected for fabrication ( Figure 2B).
- the volume and concentration of insulin loaded within the devices can be user-defined, thereby facilitating insulin loading within the devices at a larger capacity than other non-reservoir-based “smart insulin” devices that have been developed such as microneedle patches or micro/nanoparticles.
- the mechanical robustness of the hybrid material is such that the entire surface of the device is composed of the glucose-sensing material, consequently providing a continuous and large surface area for glucose-binding without the need for harsh, multi-step surface modification procedures or additional mechanically reinforcing components within the device.
- a continuous glucose-sensing surface should facilitate more rapid and robust glucose-detection and subsequent insulin release.
- the mechanical strength of the hybrid material may be enhanced compared to pure hydrogel films (Figure 3B) and may demonstrate remarkable recoverability from deformation under cyclic loading (Figure 3C). While the energy dissipated in the second cycle was observed to be lower than that of the first cycle, it remained approximately constant for subsequent cycles. It is possible that rearrangements in the interpenetrating network structure during the first cycle contributed to this phenomenon, and this reconfiguration contributes to the material’s ability to maintain elasticity and strength under subsequent cyclic loading.
- these features contributed to the material’s ease of handling compared to its pure hydrogel counterpart when formed into a cannula (Figure 3A).
- control PU devices demonstrated negligible glucose-responsive insulin release and did not support pulsatile insulin delivery ( Figures 7A, 7D, 7E, 7F).
- Figures 7A, 7D, 7E, 7F Collectively, without being bound by any theory, these results may substantiate that the ends-sealed cannulas made of the hybrid material supported glucose-mediated insulin release in vitro under physiologically relevant parameters, with the fast insulin release kinetics showing great potential to regulate BGLS in real time effectively.
- mice were assigned to be treated with either a subcutaneous injection of PBS or insulin (0.05 mg) or with a subcutaneous implantation of an insulin reservoir device either with the glucose responsive properties (PBA device) or the pure elastomer control (PU), both at a dose of 1.5 mg of insulin.
- PBA device glucose responsive properties
- PU pure elastomer control
- the blood glucose levels of all treated groups decreased to below 200 mg/dL within one hour of receiving insulin, indicating the rapid blood sugar reducing capacities of insulin-based treatments (Figure 8C).
- mice treated with an insulin injection showed only transient glycemic control, with the mice returning to hyperglycemic BGLs within two-to-thrcc hours after receiving the insulin injection (Figure 8F).
- mice with insulin reservoirs showed prolonged glycemic control, on average lasting for three days (Figure 8C).
- FPBA-based devices were shown both to prevent hypoglycemic episodes, which remains one of the outstanding challenges of many “smart” insulin delivery technologies, and maintained glucose levels within the normal range (100 mg/dL ⁇ x ⁇ 200 mg/dL) for approximately 72 hours before the mice returned to hyperglycemic BGLS ( Figures 8D, 8G).
- IPGTTs intraperitoneal glucose tolerance tests
- a core-shell cannula that attaches to an insulin reservoir was designed; the previously described glucose-responsive membrane is wrapped around an inner silicone lumen to allow this outer layer to act as a glucose-responsive reservoir for controlled basal (e.g., long-term) insulin release while the inner, open-ended lumen allows for rapid infusions of large quantities of insulin, akin to bolus (e.g., mealtime) insulin delivery.
- basal e.g., long-term
- bolus e.g., mealtime
- this new cannula/device design may support glucose-responsive basal insulin infusion and bolus insulin delivery when evaluated in vitro under physiologically relevant glucose-concentrations.
- Glucose responsive insulin cannula [0164]
- cannulas for home insulin delivery are made of stainless steel or flexible soft polymers. Insulin flows from the distal tip of the cannula when a small basal dose or a larger meal- time bolus is delivered. A pool of insulin forms under the skin which is taken up into the blood and lymphatic systems. Slowed absorption and insulin degradation due to inflammatory cell enzymatic activity contribute to decreased insulin effectiveness. Similarly, unexpected hyperglycemia can also occur due to a blockage of insulin flow through the cannula or tubing, which are thought to underly approximately 30% of decisions to change an insulin infusion set during clinical trials.
- the cannula When the cannula experiences an occlusion or kink, it is inferred based on hyperglycemia or increased resistance to insulin dosage sensed by the pump prompting an alarm on the pump.
- Insulin infusion sets are to be changed every 2-3 days according to FDA guidance. Even within a 2-to-3-day wear period, unexplained hyperglycemia occurs sometimes due to cannula non-function.
- the glucose-responsive material may significantly impact the way insulin dependent diabetes is treated with constant subcutaneous infusion. As a cannula, the material may improve absorption of insulin by distributing the bolus of liquid in the subcutaneous tissue, and the glucose-responsive changes in permeability of the cannula will reduce insulin adsorption to the cannula.
- the material may allow insulin to percolate to any area where the tissue will expand, and this flow could continue despite closure of the main lumen, due to permeability along the wall of the cannula.
- Extended functional wear may result from fibrosis reducing intrinsic properties of the novel polymer. Without being bound by any theory, fewer malfunctions and reduced infusion site changes may reduce stress on diabetic patients and caregivers, improving the sense of wellbeing, improving overall health.
- the entirety of the core-shell wall is permeable and participates in the diffusion based, glucose-binding insulin release process (Figure 15).
- Such a design can provide multiple pathways for the infused insulin to be delivered in the case of kinking and subsequent occlusion (or partial occlusion), a leading cause of failure for cannulas in many tethered and patchpump insulin delivery technologies. Without being bound by any theory, this may likewise reduce the need for premature catheter changes due to clogging, which may substantially contribute to patient’s well-being.
- the inner open-ended silicone core allows for rapid injections of large quantities of insulin to support mealtime (bolus) insulin requirements (Figure 14A).
- the inner core also allows for an introducing needle to pierce through the lumen of the prototype for direct subcutaneous insertion without disturbing the reservoir-function of the glucose-responsive layer ( Figure 14G). This may eliminate the need of implantation required of the previous iterations of the cannula (e.g., the ends-sealed and the transcutaneous, externally refillable cannula).
- the phenylboronic acid-based (e.g., FPBA) glucose sensing mechanism differs from conventional glucose-oxidase based CGMs, it can be postulated that this design may also minimize (and even potentially eliminate) concerns of interference to glucose-sensing from preservatives used in insulin formulations.
- the core-shell, glucose-responsive cannula was attached to an insulin reservoir ( Figure 14B).
- the outer lumen of the cannula is fed the insulin from the reservoir to support basal insulin needs, while the inner lumen remains open to allow for rapid infusion of larger insulin quantities needed during bolus insulin infusion ( Figures 14C, 14D).
- the two port-design on the insulin reservoir facilitates the distinction between the two functions of the cannula, as one port directly connects to the insulin reservoir for external refilling of the reservoir, while the other connects to the inner core of the cannula for bolus infusions ( Figures 14E, 14F).
- this design may facilitate a more user-friendly insertion process of the cannula while supporting both basal and bolus insulin delivery in an electronics and software-free manner.
- the suitability of the core-shell cannula prototype to support insulin delivery was explored.
- insulin reservoirs were loaded with -200 pL of insulin (10 mg/mL), and then placed the insulin-filled devices in release mediums with different physiologically relevant glucose concentrations (e.g., 0, 100, or 400 mg/dL).
- FPBA e.g., the glucose-binding monomer
- PU-based core-shell cannulas showed negligible glucose-responsive insulin release, instead releasing similar quantities of insulin regardless of the glucose-concentration in the release medium ( Figures 16A, 16B).
- the glucose-responsive cannula was attached to the mouse VABTM button (INSTECH) ( Figures 23A, 23B).
- the mouse VABTM is a transcutaneous button that — when attached to our glucose-responsive cannula — permits quick, painless, aseptic filling and refilling of insulin in the inserted cannula via a syringe ( Figure 23A).
- Figure 24B we can slip-on a medical grade silicone tube to the non-sealed end of the cannula ( Figure 24B), which is then used to tether the cannula to the 22ga connector under the disk of the VABTM transcutaneous button, creating a closed system ( Figure 23A).
- the polyester felt attached to the transcutaneous button additionally aids to hold the device in place under the skin which may facilitate improved patency.
- the glucoseresponsive cannula when attached to the button, provides the composite device with glucose- dcpcndcnt insulin delivery ( Figure 23 A).
- the transcutaneous button-connected cannulas were inserted under the skin of STZ-induced diabetic mice ( Figure 23B, 24C, 24D). Approximately 10U ( ⁇ 50pL (7.5 mg/mL)) of fresh insulin were used to refill the cannula twice daily. The insulin solution remaining in the device was removed prior to administration of the fresh insulin dose.
- the BGLs of the mice started decreasing 30 minutes after the cannula insertion, with the stable establishment of normoglycemia (e.g., BGLs within the 100-200 mg/dL range) occurring after approximately one hour (Figure 23C).
- Non-invasive insulin delivery devices are garnering significant attention to improve the standard of care of self-directed insulin delivery therapies.
- the intravaginal space is a promising site for both local and systemic drug delivery and represents an interesting, non- invasive, administration route for compounds with poor oral bioavailability (e.g. proteins).
- compounds with poor oral bioavailability e.g. proteins
- Slightly modifying the dip-coating method used to construct insulin delivery devices is conducible to forming ring-shaped hybrid devices reinforced with silicone molds to create an intravaginal insulin delivery ring ( Figure 25).
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Abstract
This disclosure relates to processes for preparing responsive materials and devices that are useful in the chemical, biological, and biomedical arts, such as in the manufacture of materials and devices and delivery of a therapy or drug. In particular, the present disclosure pertains to novel systems and methods for insulin delivery using glucose-responsive materials and devices.
Description
SYSTEMS AND METHODS FOR GLUCOSE-RESPONSIVE INSULIN DELIVERY
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority under 35 U.S.C. § 119(e) to U. S. Provisional Application Serial No. 63/327,734 filed on April 5, 2022, the entire disclosure of which is incorporated herein by reference.
BACKGROUND AND SUMMARY OF INVENTION
[0002] Treatment of glucose-mediated diseases in patients is an important medical need. Patients with a healthy pancreas demonstrate well-functioning pancreatic interactions that play a key role in ensuring glucose homeostasis, with the pancreas producing and releasing hormones (e.g., insulin and glucagon) in response to physiological fluctuations in blood glucose levels (BGLs). However, if a patient has type 1 diabetes (T1D), the autoimmune destruction of insulin-producing P-cells in the pancreas results in a loss of glycemic control, hi the absence of a cure, reversing insulin deficiency is primarily achieved through the lifelong administration of exogenous insulin via subcutaneous insulin infusions or multiple daily insulin injections.
[0003] Unfortunately, insulin replacement therapies have their own limitations, including the risk of hypoglycemia and hyperglycemia from patient-directed excess or insufficient dosing. These limitations continue to pose significant barriers in achieving desirable BGL control with insulin monotherapy. Moreover, ideal diabetes management is contingent upon strict and frequent compliance to psychologically straining caretaking protocols, imposing an incredible burden of self-care on T1D patients. As such, there is an urgent need for (new) technologies and therapies that can mimic dynamic P-cell function by affording desirable glycemic control through continual, autonomous insulin delivery with minimal burden to the patient.
[0004] In recent years, “smart” insulin-delivery devices have been discussed to possibly provide glycemic control in a similar fashion to an artificial pancreas. For example, microneedles, injectable hydrogels, reservoir devices, and ingestible micro/nano-capsules that deliver insulin in response to an external stimulus such as pH, temperature, radiation, mechanical force, and light have been developed. However, these next-generation technologies have complicated manufacturing procedures, reduced insulin loading capacities, and inadequacies in vivo for glucose-responsive behaviors. As a result, the next-generation technologies have demonstrated
sub-optimal glycemic control in patients. Therefore, there exists a need for new devices that are capable of delivering therapeutic agents such as insulin in a safe and efficient manner.
[0005] High mechanical strength and ready permeability to biological molecules (e.g. glucose and insulin) are two critical criteria for developing an implantable glucose-responsive insulin delivery device. However, these properties generally do not coexist within the same material and, instead, can even compromise each other. For instance, elastomers are known to have robust mechanical properties and stability in in vivo environments but suffer from poor permeability. Conversely, despite many efforts to construct tough hydrogel materials, hydrogels can have desirable permeability properties but poor mechanical properties and stability when exposed to an in vivo environment.
[0006] Therefore, combining elastomers and hydrogels on a molecular level through an interpenetrating network hybrid material can provide a balance between mechanical strength and selective permeability towards biomolcculcs (sec Figures 1A-1B). Accordingly, the present disclosure provides devices that possess desirable properties and can be utilized to overcome the shortcomings known in the art. Moreover, an efficient one-pot strategy for constructing a device comprising elastomer-hydrogel material using a solvent exchange process is also provided in the present disclosure (Figure 1A).
[0007] Further functionalization with phenylboronic acid (PBA) or with 4-carboxy-3- fluorophenylboronic acid (FPBA) can provide the devices with glucose-responsive changes in permeability. For instance, under hyperglycemic conditions, binding of glucose to PBA in the device can provide an increase in negative charge density, thereby increasing the permeability of the material via volumetric swelling of the carrier matrix to release enclosed insulin (Figure IB). Meanwhile, swelling can be reversed under hypoglycemic conditions from a loss of negativenegative charge repulsion, thus mitigating a potential risk of over-dosing on insulin on the return to normoglycemia. The simple fabrication processes described herein are conducive to scale-up or scale-down requirements, feasibly allowing for user-defined selection of loaded insulin (see Figures 2A-2B). Furthermore, the larger volume capacity of the devices can prevent the need of frequent administration of high doses of insulin to achieve similar hypoglycemic effects as subcutaneous insulin injections, which is a current limitation of several novel insulin delivery platforms. Given the simplicity in design and high potential for translation, this “electronic-free”
device may provide an improved platform for insulin delivery to mitigate some of the most longstanding challenges in insulin therapies for T1D.
[0008] Other objects, features and advantages of the present disclosure will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.
BRIEF DESCRIPTION OF THE DRAWINGS
[0009] FIGURE 1A shows a representative scheme of device fabrication to form the hydrogelelastomer hybrid material. Hydrogel monomers are dissolved within a precursor elastomer network. Crosslinking of the hydrogel network via UV irradiation traps the hydrogel within the elastomer material. After crosslinking of the elastomer network, a final interpenetrating “hybrid” material is formed. This hybrid material offers a tunable balance between mechanical strength and permeability towards insulin. FIGURE IB shows a representative scheme of glucose-responsive mechanism. Binding of glucose to the hydrogel-elastomer material occurs via the fluorophenylboronic acid (FPBA) monomer incorporated in the hydrogel network. Binding of glucose and FPBA renders the matrix more hydrophilic while increasing the negative charge density of the system. This increase in negative charge density increases the osmotic pressure in the system, leading to volumetric swelling of the material. The subsequent increase in permeability allows for enclosed insulin to be released.
[0010] FIGURE 2 A shows a representative scheme of the one-pot, dip-coating cannula fabrication procedure. FIGURE 2B shows an image of different sized ends-closed cannulas filled with water. [0011] FIGURE 3A shows an image of a cannula after removal from the fabrication mold (top). The cannula is mechanically robust and can be manually stretched without breakage (bottom). FIGURE 3B shows a graph of tensile stress vs tensile strain of the hybrid material as a function of hydrogel concentration (w/v%). FIGURE 3C shows a graph of loading- unloading curve of a hydrogel-elastomer sheet made from 12.5% (w/v%) elastomer and 12% (w/v%) hydrogel.
[0012] FIGURE 4A shows a graph of fracture energy of the hybrid material as a function of hydrogel concentration. The elastomer (PU-D3) concentration is fixed at 12.5% (w/v%). Data
points are means ± SD (n = 3). FIGURE 4B shows a graph of ultimate tensile strength of the hybrid material as a function of hydrogel concentration. The elastomer (PU-D3) concentration is fixed at 12.5% (w/v%). Data points are means ± SD (n = 3). FIGURE 4C shows a graph of Young’s modulus of the hybrid material as a function of hydrogel concentration. The elastomer (PU-D3) concentration is fixed at 12.5% (w/v%). Data points are means ± SD (n - 3).
[0013] FIGURE 5A shows a graph of BGL-reducing activity of freshly prepared insulin, and insulin extracted from freshly prepared ends-sealed cannulas. FIGURE 5B shows a graph of BGL- reducing activity from insulin stored at 37 °C for one week in diabetic mice (n=5). Initial BGLs were compared with BGLs at 60 min post injection of the insulin (0.05mg). FIGURE 5C shows a graph of BGL-reducing activity from insulin stored at 4 °C for 4 weeks. Initial BGLs were compared with BGLs at 60 min post injection of the insulin (0.05mg).
[0014] FIGURE 6A shows an image of the hybrid glucose-responsive material membrane. FIGURE 6B shows a graph of glucose concentration-dependent glucose binding ability of control elastomer membranes (PU). Data points represent mean +/- SD (n=3). FIGURE 6C shows a graph of glucose concentration-dependent glucose binding ability of glucose-responsive sheets (FPBA). Data points represent mean +/- SD (n=3). Statistical significance was calculated using Two-way ANOVA. * p< 0.05, ** p< 0.01, *** p < 0.001. FIGURE 6D shows a graph of the comparison of glucose absorbed by control (PU) and glucose-responsive (FPBA) sheets following Ih exposure to 200 mg/dL of glucose measured via a glucometer (blue) and a GOx assay (red).
[0015] FIGURE 7A shows a graph of the results of in vitro insulin release from ends-closed cannulas made of control (PU) materials in clinically relevant glucose concentrations. The glucose concentrations were set at 0, 100, and 400 mg/dL. Data points represent mean +/- SD (n=5). Statistical significance was calculated using Two-way ANOVA, # denotes a statistical difference from 100 mg/mL (p< 0.05). FIGURE 7B shows a graph of the results of in vitro insulin release from ends-closed cannulas made of glucose-responsive (FPBA) materials in clinically relevant glucose concentrations. The glucose concentrations were set at 0, 100, and 400 mg/dL. Data points represent mean +/- SD (n=5). FIGURE 7C shows a graph of pulsatile insulin release from ends- closed cannulas made of control (PU) and glucose-responsive (FPBA) materials by alternating the glucose concentration. The devices were incubated with each solution for 15 minutes before alternated. Data points represent mean +/- SD (n=5). FIGURE 7D shows a line graph of in vitro accumulated release of insulin from ends-closed cannulas made of control (PU) materials loaded
with 0.750 mg (50 pL of 15 mg/mL) of insulin under different glucose concentrations. FIGURE 7E shows a bar graph of in vitro accumulated release of insulin from ends-closed cannulas made of control materials loaded with 0.750 mg (50 pL of 15 mg/mL) of insulin under different glucose concentrations. FIGURE 7F shows a graph of pulsatile insulin release from control ends-closed cannulas loaded with 1.5 mg of insulin by alternating the glucose concentration for three consecutive cycles; cannulas were incubated in each solution for 15 min. FIGURE 7G shows a line graph of in vitro accumulated release of insulin from ends-closed cannulas made of glucoseresponsive materials loaded with 0.750 mg (50 pL of 15 mg/mL) of insulin under different glucose concentrations. FIGURE 7H shows a bar graph of in vitro accumulated release of insulin from ends-closed cannulas made of glucose-responsive materials loaded with 0.750 mg (50 pL of 15 mg/mL) of insulin under different glucose concentrations. Data points are means ± SD (n = 3). ns p > 0.05, * p < 0.05, * p < 0.01 , *** p < 0.001 , **** p < 0.0001. FIGURE 71 shows a graph of pulsatile insulin release from glucose-responsive ends-closed cannulas loaded with 1.5 mg of insulin by alternating the glucose concentration for three consecutive cycles; cannulas were incubated in each solution for 15 min.
[0016] FIGURE 8 A shows a representative scheme of the in vivo timeline for ends-closed cannula trial in diabetic mice. FIGURE 8B shows a representative image of the method of use of the subcutaneously implanted hybrid-membrane device. FIGURE 8C shows a graph of blood glucose levels of type 1 diabetic mice treated with subcutaneously injected PBS (100 pL), insulin (0.05 mg), or insulin loaded devices. Insulin loaded devices included PU devices for control and PBA as glucose-responsive devices; both were filled with 1.5 mg (100 pL of 15 mg/mL) of insulin. Data points are means +/- SD. (n=5). FIGURE 8D shows a graph of time spent in normoglycemia per treatment group; normoglycemia is defined as BGLs within 100 mg/dL < x < 200 mg/dL. Statistical significance between groups was calculated. FIGURE 8E shows a graph of the survival curves for control and glucose-responsive ends-sealed cannulas. Data points are means +/- SD. (n=5). FIGURE 8F shows a graph of mice given subcutaneous insulin injections quickly return to hyperglycemic BGLs, while cannula-implanted mice continue controlling BGLs. Data points are means ± SD (n = 5 mice). FIGURE 8G shows a graph of blood glucose levels of glucoseresponsive cannula treated mice (FPBA). BGLs were controlled within the normoglycemic range throughout the three-day period. Control mice (PU) fell below the range into hypoglycemic levels.
[0017] FIGURE 9A shows a graph of in vivo intraperitoneal glucose tolerance test (IPGTT) in healthy mice and diabetic mice at 1 h post-administration of control ends-closed cannulas (PU, n=5) or glucose-responsive ends-closed cannulas (FPBA). Glucose dose: 1.5 g kg.-1 FIGURE 9B shows a graph of responsiveness to IPGTT in terms of area under the (AUC) in 120 min, with the baseline set at the 0-min blood glucose reading. Data points are means +/- SD. (n=5). FIGURE 9C shows a graph of serum insulin levels and BGLs following IPGTT test at a dose of 1.5 g kg.-1 of glucose for FPBA treated mice. Data points are means ± SD (n = 5 mice).* p < 0.05, *** p < 0.001, **** p < 0.0001. The normoglycemic range is defined as BGLs within 100 mg/dL < x < 200 mg/dL. FIGURE 9D shows representative live images of mice injected with insulin or implanted with insulin-containing PU devices for control and FPBA as glucose-responsive devices following subcutaneous injection (0.05 mg) or implantation with an ends-closed cannula (1.5 mg) at time of treatment (t=0), two days after treatment (t=48h), and one week after treatment (t=168h). Insulin was labeled with Cy5. Grey area represents the normoglycemic range as defined by BGLs within 100 mg/dL < x < 200 mg/dL. FIGURE 9E shows a graph of blood glucose levels of type 1 diabetic mice treated with insulin or insulin loaded PU devices for control and FPBA as glucose-responsive devices. Data points are means +/- SD. (n=4 for PBA device, n=3 for injection and PU device). FIGURE 9F shows a graph of the evaluation of BGL reducing potential of Cy5-labeled insulin one hour following subcutaneous injection (0.05 mg) in diabetic mice. Cy5-labeled insulin was stored at 4°C prior to injection. Native insulin refers to a freshly prepared insulin solution stored at 4°C prior to injection. Data points are means ± SD (n = 6).
[0018] FIGURE 10 shows a graph of relative average radiant efficiency of live Cy5-labeled insulin imaging over time of type 1 diabetic mice. Data points are means +/- SD. (n=4 for PBA device, n=3 for injection and PU device).
[0019] FIGURE 11A shows an image of ends-closed cannula prior to (left) and immediately after implantation (right) in the subcutaneous space. Mice were shaved and prior to implantation. FIGURE 11B shows an image of H&E (top) and Masson Trichrome (bottom) staining of a retrieved ends-sealed cannula one week after subcutaneous implantation. FIGURE 11C shows images of ends-sealed cannula prior to implantation (right) and during retrieval (left) after one- week implantation. After a minor incision, the cannulas can be retrieved completely without tissue adhesion or major deformation.
[0020] FIGURE 12 shows images of H&E staining of ends-sealed cannula post-retrieval at one week from the subcutaneous space of C57BL/6 diabetic mice. An image of the longitudinal section of the cannula is shown (center), and some images from the cannula-host boundary are shown in the surrounding magnified images. The asterisk (*) indicates the host side of the device-host boundary.
[0021] FIGURE 13 A shows images of H&E staining of ends-sealed cannula one week from the subcutaneous space of C57BL/6 mice, emphasizing the initial cell adhesion response at the lowest magnitude. Arrows indicate cell attachment; the asterisk (*) indicates the host side of the devicehost boundary. FIGURE 13B shows images of H&E staining of ends-sealed cannula one week from the subcutaneous space of C57BL/6 mice, emphasizing the initial cell adhesion response at a magnitude between the lowest and highest selected magnitudes. Arrows indicate cell attachment; the asterisk (*) indicates the host side of the device-host boundary. FIGURE 13C shows images of H&E staining of ends-sealed cannula one week from the subcutaneous space of C57BL/6 mice, emphasizing the initial cell adhesion response at the highest magnitude. Arrows indicate cell attachment; the asterisk (*) indicates the host side of the device-host boundary.
[0022] FIGURE 14A shows a representative scheme of the core-shell cannula is designed such that it contains an open inner lumen (left) and a sealed, glucose-responsive membrane that is wrapped around the inner lumen. FIGURE 14B shows a representative scheme of the open inner lumen (left) is connected to an external bolus port on the insulin reservoir via a silicone tube, allowing for rapid infusions of large quantities of insulin. Basal insulin delivery (right) is supported by the glucose-responsive membrane. To prevent leaking, the distal end of the glucose-responsive membrane is sealed shut onto the open inner lumen. The proximal end is left open to the insulin reservoir, allowing for diffusion of insulin to the cannula. The permeability of the glucoseresponsive membrane changes according to local changes in glucose, thereby supporting dynamic basal insulin infusions. FIGURE 14C shows a representative image of the core-shell cannula attached to the bottom of the insulin reservoir. The glucose-responsive membrane (clear) is conical to maximize volume for insulin diffusion while enabling insertion via an introducing needle. FIGURE 14D shows a representative image of compiled device, with silicone tubing extending outwards of insulin reservoir to demonstrate the bolus infusion port. Ruler units in all images are in cm. FIGURE 14E shows a representative top and bottom images of the dual-port reservoir prior to closing. Ruler units in all images are in cm. FIGURE 14F shows a representative top and bottom
images of the dual-port reservoir after closing. Ruler units in all images are in cm. FIGURE 14G shows a representative image of a 27ga needle through the inner lumen of an elongated core-shell cannula prototype to demonstrate needle-guided insertion.
[0023] FIGURE 15 shows a representative images to qualitatively monitor diffusion from the core- shell cannula. The device was inserted into an alginate/acrylamide tough hydrogel skin mimic (left). Over time, the dye can be seen permeating along the entire length of the cannula, indicating that the entire shell of the cannula is permeable.
[0024] FIGURE 16A shows a graph of in vitro accumulated release of insulin from core- shell cannula devices made of control materials loaded with 200 pL of 10 mg/mL insulin under different glucose concentrations. Data points are means ± SD (n = 5); ns= p> 0.05, * p<0.05, ** p< 0.01, *** p < 0.001. FIGURE 16B shows a graph of in vitro accumulated release of insulin from coreshell cannula devices made of glucose-responsive materials loaded with 200 pL of 10 mg/mL insulin under different glucose concentrations. Data points arc means ± SD (n = 5); ns= p> 0.05,
* p<0.05, ** p< 0.01, *** p < 0.001. FIGURE 16C shows a graph of pulsatile insulin release from FPBA core-shell cannulas loaded with 200 pL of 10 mg/mL insulin by alternating the glucose concentration from high (H= 400 mg/dL) glucose to low (L=100 mg/dL) glucose for three consecutive cycles. The cannulas were incubated in each solution for 15 min or 30 min. Data points are means + SD (n = 5); ns- p> 0.05, * p<0.05, ** p< 0.01, *** p < 0.001. FIGURE 16D shows a graph of BGL-reducing activity of freshly prepared insulin, insulin extracted from freshly prepared core-shell cannulas, and from insulin stored in insulin reservoirs of core-shell cannulas for 1 week at room temperature in diabetic mice. Initial BGLs were compared with BGLs at 30 min and 60 min post subcutaneous injection of the insulin (0.05mg). Data points are means ± SD (n = 5); ns= p> 0.05, * p<0.05, ** p< 0.01, *** p < 0.001.
[0025] FIGURE 17A shows a bar graph of in vitro accumulated release of insulin from core-shell cannula devices made glucose-responsive materials loaded with 200 pL of U100 inulin (3.47 mg/mL) under different glucose concentrations. Data points are means ± SD (n = 5); ns- p> 0.05,
* p<0.05, ** p<0.01. FIGURE 17B shows a line graph of in vitro accumulated release of insulin from core-shell cannula devices made glucose-responsive materials loaded with 200 pL of U100 inulin (3.47 mg/mL) under different glucose concentrations. Data points are means ± SD (n = 5); ns= p> 0.05, * p<0.05, ** p<0.01. FIGURE 17C shows a graph of basal insulin release rate distribution by age from insulin pump users. Graph reproduced from TTDEPOOL.
[0026] FIGURE 18A shows a bar graph of in vitro accumulated release of insulin from cylindrical core-shell cannula devices made glucose-responsive materials loaded with 200 pL of U100 insulin (3.47 mg/mL) under different glucose concentrations. Data points are means ± SD (n = 5); ns= p> 0.05, * p<0.05, **p<0.01, *** p<0.001. FIGURE 18B shows a line graph of in vitro accumulated release of insulin from cylindrical core-shell cannula devices made glucose-responsive materials loaded with 200 pL of U100 insulin (3.47 mg/mL) under different glucose concentrations. Data points are means ± SD (n = 5); ns- p> 0.05, * p<0.05, **p<0.01, *** p<0.001. FIGURE 18C shows a graph of pulsatile insulin release from FPBA cylindrical core-shell cannulas loaded with 200 μL of 3.47 mg/mL insulin by alternating the glucose concentration from high (H= 400 mg/dL) glucose to low (L=100 mg/dL) glucose for three consecutive cycles. The cannulas were incubated in each solution for 15 min. FPBA represents glucose-responsive materials and while PU designates control samples. Data points are means ± SD (n = 5); ns= p> 0.05, * p<0.05, **p<0.01 , *** p<0.001.
[0027] FIGURE 19 shows a graph of in vitro insulin accumulated from 2U bolus insulin injection through core-shell device compared to a direct injection into the collection buffer. Bolus injections 1-3 were performed 5 hours apart to simulate three meal-supported insulin injections. Data points are means ± SD (n = 5); ns= p> 0.05.
[0028] FIGURE 20A shows graphs of ultimate tensile stress (MPa), tensile strain (mm/mm), and Young’s modulus (MPa) of the elastomer as a function of concentration in the precursor solution (w/v%). The materials were evaluated after swelling for three days in PBS at room temperature under static conditions. Generally, an increase in concentration causes an increase in viscosity, decreasing elasticity while increasing ultimate tensile strength. Material properties are generally maintained after exposure to in vivo conditions for concentrations in the range of 10-30% (w/v%). Data points are means ± SD (n = 3). FIGURE 20B shows graphs of ultimate tensile stress (MPa), tensile strain (mm/mm), and Young’s modulus (MPa) of the elastomer as a function of concentration in the precursor solution (w/v%). The materials were evaluated after swelling for three days in PBS at 37C, RPM 70 to simulate in vivo conditions.
[0029] FIGURE 21 A shows a graph of in vitro evaluation of water content before and after glucose exposure. Equilibrium water content of control elastomer (PU) and glucose-responsive materials (FPBA) after swelling in PBS. Data points are means ± SD (n = 3). ** p< 0.01, *** p< 0.001, **** p < 0.0001 . FIGURE 21 B shows a graph of in vitro evaluation of water content before and after
glucose exposure. Equilibrium water content of control elastomer (PU) and glucose-responsive materials (FPBA) after swelling in PBS containing glucose (0-400 mg/dL) (right) for three days at room temperature. Data points are means ± SD (n = 3). ** p< 0.01, *** p< 0.001, **** p < 0.0001. [0030] FIGURE 22A shows a graph of effects of insulin concentration on in vitro insulin release rates. Insulin release from ends-sealed control cannulas (PU) loaded with ~50pL of 25 mg/mL of insulin. Cannulas were incubated in high (400 mg/dL) or low (100 mg/dL) glucose solutions in 2mL PBS, pH 7.4 at 37C, RPM 70 for the duration of the experiment. Linear regression lines were fitted to each sample to determine release rates of insulin per hour (equations shown). Data points are means ± SD (n = 3). FIGURE 22B shows a graph of effects of insulin concentration on in vitro insulin release rates. Insulin release from ends-sealed glucose-responsive cannulas (FPBA) loaded with ~50pL of 25 mg/mL of insulin. Cannulas were incubated in high (400 mg/dL) or low (100 mg/dL) glucose solutions in 2mL PBS, pH 7.4 at 37C, RPM 70 for the duration of the experiment. Linear regression lines were fitted to each sample to determine release rates of insulin per hour (equations shown). Data points are means ± SD (n = 3). FIGURE 22C shows a graph of effects of insulin concentration on in vitro insulin release rates. Insulin release from ends-sealed control cannulas (PU) loaded with ~50pL of 10 mg/mL of insulin. Cannulas were incubated in high (400 mg/dL) or low (100 mg/dL) glucose solutions in 2mL PBS, pH 7.4 at 37C, RPM 70 for the duration of the experiment. Linear regression lines were fitted to each sample to determine release rates of insulin per hour (equations shown). Data points are means ± SD (n = 3). FIGURE 22D shows a graph of effects of insulin concentration on in vitro insulin release rates. Insulin release from ends- sealed glucose-responsive cannulas (FPBA) loaded with ~50pL of 25 mg/mL of insulin (top) and with ~50pL of 10 mg/mL of insulin (bottom). Cannulas were incubated in high (400 mg/dL) or low (100 mg/dL) glucose solutions in 2mL PBS, pH 7.4 at 37C, RPM 70 for the duration of the experiment. Linear regression lines were fitted to each sample to determine release rates of insulin per hour (equations shown). Data points are means ± SD (n = 3).
[0031] FIGURE 23 A shows representative schematic illustration of the method of action of the externally refillable, transcutaneous cannula. (1) The mouse VAB™ transcutaneous button has a 22ga connector through which the glucose-responsive cannula can be attached to via a silicone adapter. (2) The external adapter can then be used for quick, aseptic filling and refilling of insulin of the implanted cannula via a syringe. The cannula can then moderate insulin release in a glucoseresponsive fashion. FIGURE 23B shows a representative schematic illustration of timeline for
transcutaneous, externally refillable cannula trial in diabetic mice. FIGURE 23C shows a graph of BGLs of diabetic mice implanted with glucose-responsive cannulas (FPBA) loaded with 0.375 mg (50pL of a 7.5 mg/mL solution) of insulin (n=10) or injected subcutaneously (n=3) with insulin (0.05mg). FIGURE 23D shows a graph of individual BGL curves for mice with the transcutaneous cannula; black arrows indicate when a fresh infusion of insulin (0.375 mg); red arrow indicates when insulin was removed from the cannula. Grey area represents the normoglycemic range as defined by BGLs within 100 mg/dL < x < 200 mg/dL. FIGURE 23E shows a graph of individual BGL curves for subcutaneous injections of insulin; black arrows indicate when a fresh subcutaneous injection of insulin (0.05mg) was administered. Grey area represents the normoglycemic range as defined by BGLs within 100 mg/dL < x < 200 mg/dL.
[0032] FIGURE 24A shows a representative schematic illustration of the externally refillable, transcutaneous cannula by attaching a one-end sealed cannula to a commercially available mouse VAB™ button (INSTECH) (1) to externally refill (2) the implanted cannula using the aseptic, external filling port. FIGURE 24B shows images of top-down view of completed device where the cannula is filled with blue-dyed water to demonstrate a filled cannula (top), and the underside of the device (bottom). The cannula is connected to the mouse VAB™ button (INSTECH) via a silicone tube that is glued onto the cannula. FIGURE 24C shows images of the device before (left) and after (middle) implantation. The red cap (right) is used to close the refilling port and protect the button when group housing mice. FIGURE 24D shows images of the device prior to (top) and after (bottom) refilling.
[0033] FIGURE 25 shows a representative image of an insulin delivery ring prototype (left) in comparison to a commercially available intravaginal ring used for birth control purposes (NuvaRing®).
DETAILED DESCRIPTION
[0034] In the present disclosure, the following terminology will be used in accordance with the definitions set forth below.
[0035] The term "about" as used herein means greater or lesser than the value or range of values stated by 10 percent, but is not intended to designate any value or range of values to only this broader definition. Each value or range of values preceded by the term "about" is also intended to encompass the embodiment of the stated absolute value or range of values.
[0036] The use of the term “or” in the claims is used to mean “and/or” unless explicitly indicated to refer to alternatives only or the alternatives are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and “and/or.”
[0037] As used in this specification and claim(s), the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”) or “containing” (and any form of containing, such as “contains” and “contain”) are inclusive or open- ended and do not exclude additional, unrecited elements or method steps.
[0038] As used herein, the term "treating" includes alleviation of the symptoms associated with a specific disorder or condition and/or preventing or eliminating said symptoms.
[0039] As used herein the terms “effective amount” or "therapeutically effective amount” of a compound refers to a nontoxic but sufficient amount of the compound to provide the desired effect. The amount that is “effective” will vary from subject to subject, depending on the age and general condition of the individual, mode of administration, and the like. Thus, it is not always possible to specify an exact “effective amount.” However, an appropriate “effective” amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation. [0040] As used herein, unless specifically provided to the contrary, % and wt. % will equally mean % by weight of the total weight.
[0041] As used herein the term “subject” means an animal including but not limited to, humans, domesticated animals including horses, dogs, cats, cattle, and the like, rodents, reptiles, and amphibians
[0042] As used herein the term “patient” means an animal including but not limited to, humans, domesticated animals including horses, dogs, cats, cattle, and the like, rodents, reptiles, and amphibians being administered a therapeutic treatment either with or without physician oversight. [0043] Various embodiments of the invention are described herein as follows. The following numbered embodiments are contemplated and are non-limiting:
1. A device comprising i) one or more hydrogel components and ii) an elastomer.
2. The device of clause 1, any other suitable clause, or any combination of suitable clauses, wherein the one or more hydrogel components comprise a glucose binding composition.
3. The device of clause 2, any other suitable clause, or any combination of suitable clauses, wherein the glucose binding composition comprises phenylboronic acid (PBA), or
wherein the glucose binding composition comprises 4-carboxy-3-fluorophenylboronic acid (FPBA), or wherein the glucose binding composition comprises PBA and FPBA.. The device of clause 2, any other suitable clause, or any combination of suitable clauses, wherein the glucose binding composition consists essentially of PBA, or wherein the glucose binding composition consists essentially of FPBA, or wherein the glucose binding composition consists essentially of PBA and FPBA. The device of clause 2, any other suitable clause, or any combination of suitable clauses, wherein the glucose binding composition consists of PBA, or wherein the glucose binding composition consists of FPBA, or wherein the glucose binding composition consists of PBA and FPBA. The device of clause 1, any other suitable clause, or any combination of suitable clauses, wherein the one or more hydrogel components comprise a crosslinker. The device of clause 6, any other suitable clause, or any combination of suitable clauses, wherein the crosslinker comprises N, N’-methylenebis(acrylamide) (MBAA). The device of clause 6, any other suitable clause, or any combination of suitable clauses, wherein the crosslinker consists essentially of MBAA. The device of clause 6, any other suitable clause, or any combination of suitable clauses, wherein the crosslinker consists of MBAA. The device of clause 1, any other suitable clause, or any combination of suitable clauses, wherein the one or more hydrogel components comprise a photo initiator. The device of clause 10, any other suitable clause, or any combination of suitable clauses, wherein the photo initiator comprises Irgacure 2959 (IR2959). The device of clause 10, any other suitable clause, or any combination of suitable clauses, wherein the photo initiator consists essentially of IR2959. The device of clause 10, any other suitable clause, or any combination of suitable clauses, wherein the photo initiator consists of IR2959. The device of clause 1, any other suitable clause, or any combination of suitable clauses, wherein the elastomer is a polyurethane. The device of clause 14, any other suitable clause, or any combination of suitable clauses, wherein the polyurethane comprises a HydroMed D3 polyurethane.
The device of clause 14, any other suitable clause, or any combination of suitable clauses, wherein the polyurethane consists essentially of a HydroMed D3 polyurethane. The device of clause 14, any other suitable clause, or any combination of suitable clauses, wherein the polyurethane consists of a HydroMed D3 polyurethane. The device of clause 14, any other suitable clause, or any combination of suitable clauses, wherein the polyurethane is selected from the group consisting of a HydroMed D7, D4, D3, DI, D6, D640 polyurethane, and combinations thereof. The device of clause 1, any other suitable clause, or any combination of suitable clauses, wherein the elastomer is a product of an elastomer solution. The device of clause 19, any other suitable clause, or any combination of suitable clauses, wherein the elastomer solution comprises a concentration of 18 wt%. The device of clause 19, any other suitable clause, or any combination of suitable clauses, wherein the elastomer solution comprises a concentration of 16-20 wt%. The device of clause 1, any other suitable clause, or any combination of suitable clauses, wherein the elastomer forms an elastomeric network. The device of clause 1, any other suitable clause, or any combination of suitable clauses, wherein the hydrogel components form a hydrogel. The device of clause 23, any other suitable clause, or any combination of suitable clauses, wherein the hydrogel is photocrosslinked. The device of clause 23, any other suitable clause, or any combination of suitable clauses, wherein the hydrogel is contained in an elastomeric network. The device of clause 25, any other suitable clause, or any combination of suitable clauses, wherein the hydrogel-elastomeric network forms an interpenetrating network. The device of clause 26, any other suitable clause, or any combination of suitable clauses, wherein the interpenetrating network is configured to release insulin. The device of clause 27, any other suitable clause, or any combination of suitable clauses, wherein the insulin can be released from any portion of the interpenetrating network. The device of clause 27, any other suitable clause, or any combination of suitable clauses, wherein the insulin can be released from one or more non-perf orated portions of the interpenetrating network.
The device of clause 1, any other suitable clause, or any combination of suitable clauses, wherein the device further comprises insulin. The device of clause 30, any other suitable clause, or any combination of suitable clauses, wherein the insulin is a fast acting insulin. The device of clause 30, any other suitable clause, or any combination of suitable clauses, wherein the insulin is a long acting insulin. The device of clause 30, any other suitable clause, or any combination of suitable clauses, wherein the insulin comprises a fast acting insulin, a long acting insulin, or a combination thereof. The device of clause 1, any other suitable clause, or any combination of suitable clauses, wherein the device is irradiated. The device of clause 34, any other suitable clause, or any combination of suitable clauses, wherein the irradiation is ultraviolet irradiation. The device of clause 1, any other suitable clause, or any combination of suitable clauses, wherein the device is configured to comprise a therapeutic agent. The device of clause 36, any other suitable clause, or any combination of suitable clauses, wherein the therapeutic agent is insulin. The device of clause 36, any other suitable clause, or any combination of suitable clauses, wherein the insulin is a fast acting insulin. The device of clause 36, any other suitable clause, or any combination of suitable clauses, wherein the insulin is a long acting insulin. The device of clause 39, any other suitable clause, or any combination of suitable clauses, wherein the insulin comprises a fast acting insulin, a long acting insulin, or a combination thereof. The device of clause 1, any other suitable clause, or any combination of suitable clauses, wherein the device is configured to contain a surfactant. The device of clause 41, any other suitable clause, or any combination of suitable clauses, wherein the surfactant is a non-ionic surfactant. The device of clause 41, any other suitable clause, or any combination of suitable clauses, wherein the surfactant comprises n-Octyl-p-d-glucoside.
The device of clause 41, any other suitable clause, or any combination of suitable clauses, wherein the surfactant consists essentially of zt-Octyl-P-d-glucoside. The device of clause 41, any other suitable clause, or any combination of suitable clauses, wherein the surfactant consists of n-Octyl-β-d-glucoside. The device of clause 1, any other suitable clause, or any combination of suitable clauses, wherein the device is configured to absorb glucose. The device of clause 46, any other suitable clause, or any combination of suitable clauses, wherein the device is a permeable device for the absorption of glucose. The device of clause 46, any other suitable clause, or any combination of suitable clauses, wherein the absorption occurs in a glucose responsive manner. The device of clause 46, any other suitable clause, or any combination of suitable clauses, wherein the absorption occurs under hypoglycemic conditions. The device of clause 46, any other suitable clause, or any combination of suitable clauses, wherein the absorption occurs under hyperglycemic conditions. The device of clause 1, any other suitable clause, or any combination of suitable clauses, wherein the device is implantable. The device of clause 51, any other suitable clause, or any combination of suitable clauses, wherein the implantable device is removable. The device of clause 1, any other suitable clause, or any combination of suitable clauses, wherein the device does not comprise a glucose-responsive plug. The device of clause 1, any other suitable clause, or any combination of suitable clauses, wherein the device is substantially free of electronics. The device of clause 1, any other suitable clause, or any combination of suitable clauses, wherein the device is a tube. The device of clause 55, any other suitable clause, or any combination of suitable clauses, wherein the tube is sealed with a thermoseal. The device of clause 55, any other suitable clause, or any combination of suitable clauses, wherein the tube is sealed at a first end of the tube, at a second end of the tube, or both. The device of clause 57, any other suitable clause, or any combination of suitable clauses, wherein the first end of the tube is sealed with a thermoseal.
The device of clause 57, any other suitable clause, or any combination of suitable clauses, wherein the second end of the tube is sealed with a thermoseal. The device of clause 57, any other suitable clause, or any combination of suitable clauses, wherein the first end of the tube is sealed with a thermoseal and the second end of the tube is sealed with a thermoseal. The device of clause 1, any other suitable clause, or any combination of suitable clauses, wherein the device is a cannula. The device of clause 1, any other suitable clause, or any combination of suitable clauses, wherein the device is a ring-shaped device. The device of clause 1, any other suitable clause, or any combination of suitable clauses, wherein the device is an intravaginal delivery device. A process for producing a device, the process comprising the steps of: a) combining one or more hydrogel components and a liquid composition comprising an elastomer to form a liquid combination, b) evaporating the liquid combination to form a hydrogel matrix, c) irradiating the hydrogel matrix to form the device. The process of clause 64, any other suitable clause, or any combination of suitable clauses, wherein the process is performed via a one-pot system. The process of clause 64, any other suitable clause, or any combination of suitable clauses, wherein the device is an interpenetrating network. The process of clause 64, any other suitable clause, or any combination of suitable clauses, wherein the liquid composition comprising an elastomer is a solution. The process of clause 67, any other suitable clause, or any combination of suitable clauses, wherein the elastomer solution comprises a concentration of 18 wt%. The process of clause 67, any other suitable clause, or any combination of suitable clauses, wherein the elastomer solution comprises a concentration of 16-20 wt%. The process of clause 64, any other suitable clause, or any combination of suitable clauses, wherein the process comprises use of a mold to form the device. The process of clause 70, any other suitable clause, or any combination of suitable clauses, wherein the liquid combination of step a) is placed in the mold.
The process of clause 70, any other suitable clause, or any combination of suitable clauses, wherein step b) is performed on the liquid combination in the mold. The process of clause 70, any other suitable clause, or any combination of suitable clauses, wherein step c) is performed on the hydrogel matrix in the mold. The process of clause 70, any other suitable clause, or any combination of suitable clauses, wherein the process further comprises a step d), wherein step d) comprises removing the device from the mold. The process of clause 74, any other suitable clause, or any combination of suitable clauses, wherein step d) comprises placing the device in water. The process of clause 64, any other suitable clause, or any combination of suitable clauses, wherein the irradiation is ultraviolet irradiation. The process of clause 64, any other suitable clause, or any combination of suitable clauses, wherein the hydrogel matrix is photocrosslinked. The process of clause 64, any other suitable clause, or any combination of suitable clauses, wherein the process further comprises a step of adding insulin to the device. The process of clause 78, any other suitable clause, or any combination of suitable clauses, wherein the insulin is a fast acting insulin. The process of clause 78, any other suitable clause, or any combination of suitable clauses, wherein the insulin is a long acting insulin. The process of clause 78, any other suitable clause, or any combination of suitable clauses, wherein the insulin comprises a fast acting insulin, a long acting insulin, or a combination thereof. The process of clause 64, any other suitable clause, or any combination of suitable clauses, wherein the process further comprises a step of adding a surfactant to the device. The process of clause 82, any other suitable clause, or any combination of suitable clauses, wherein the surfactant is a non-ionic surfactant. The process of clause 82, any other suitable clause, or any combination of suitable clauses, wherein the surfactant comprises n-Octyl-β-d-glucoside. The process of clause 82, any other suitable clause, or any combination of suitable clauses, wherein the surfactant consists essentially of n-Octyl-p-d-glucoside.
The process of clause 82, any other suitable clause, or any combination of suitable clauses, wherein the surfactant consists of n -Octyl-β-d-glucoside. The process of clause 64, any other suitable clause, or any combination of suitable clauses, wherein the one or more hydrogel components comprise a glucose binding composition. The process of clause 87, any other suitable clause, or any combination of suitable clauses, wherein the glucose binding composition comprises phenylboronic acid (PBA), or wherein the glucose binding composition comprises 4-carboxy-3-fluorophenylboronic acid (FPBA), or wherein the glucose binding composition comprises PBA and FPBA. The process of clause 87, any other suitable clause, or any combination of suitable clauses, wherein the glucose binding composition consists essentially of PBA, or wherein the glucose binding composition consists essentially of FPBA, or wherein the glucose binding composition consists essentially of PBA and FPBA. The process of clause 87, any other suitable clause, or any combination of suitable clauses, wherein the glucose binding composition consists of PBA, or wherein the glucose binding composition consists of FPBA, or wherein the glucose binding composition consists of PBA and FPBA. The process of clause 64, any other suitable clause, or any combination of suitable clauses, wherein the one or more hydrogel components comprise a crosslinker. The process of clause 91, any other suitable clause, or any combination of suitable clauses, wherein the crosslinker comprises N, N’-methylenebis(acrylamide) (MBAA). The process of clause 91, any other suitable clause, or any combination of suitable clauses, wherein the crosslinker consists essentially of MBAA. The process of clause 91, any other suitable clause, or any combination of suitable clauses, wherein the crosslinker consists of MBAA. The process of clause 64, any other suitable clause, or any combination of suitable clauses, wherein the one or more hydrogel components comprise a photo initiator. The process of clause 95, any other suitable clause, or any combination of suitable clauses, wherein the photo initiator comprises Irgacure 2959 (IR2959). The process of clause 95, any other suitable clause, or any combination of suitable clauses, wherein the photo initiator consists essentially of 1R2959.
The process of clause 95, any other suitable clause, or any combination of suitable clauses, wherein the photo initiator consists of IR2959. The process of clause 64, any other suitable clause, or any combination of suitable clauses, wherein the elastomer is a polyurethane. . The process of clause 99, any other suitable clause, or any combination of suitable clauses, wherein the polyurethane comprises a HydroMed D3 polyurethane. . The process of clause 99, any other suitable clause, or any combination of suitable clauses, wherein the polyurethane consists essentially of a HydroMed D3 polyurethane.. The process of clause 99, any other suitable clause, or any combination of suitable clauses, wherein the polyurethane consists of a HydroMed D3 polyurethane. . The process of clause 99, any other suitable clause, or any combination of suitable clauses, wherein the polyurethane is selected from the group consisting of a HydroMed D7, D4, D3, DI, D6, D640 polyurethane, and combinations thereof. . The process of clause 64, any other suitable clause, or any combination of suitable clauses, wherein the elastomer forms an elastomeric network. . The process of clause 64, any other suitable clause, or any combination of suitable clauses, wherein the device is configured to absorb glucose. . The process of clause 105, any other suitable clause, or any combination of suitable clauses, wherein the device is a permeable device for the absorption of glucose.. The process of clause 105, any other suitable clause, or any combination of suitable clauses, wherein the absorption occurs in a glucose responsive manner. . The process of clause 105, any other suitable clause, or any combination of suitable clauses, wherein the absorption occurs under hypoglycemic conditions. . The process of clause 105, any other suitable clause, or any combination of suitable clauses, wherein the absorption occurs under hyperglycemic conditions. . The process of clause 64, any other suitable clause, or any combination of suitable clauses, wherein the device is implantable. . The process of clause 110, any other suitable clause, or any combination of suitable clauses, wherein the implantable device is removable. . The process of clause 64, any other suitable clause, or any combination of suitable clauses, wherein the device does not comprise a glucose-responsive plug.
13. The process of clause 64, any other suitable clause, or any combination of suitable clauses, wherein the device is substantially free of electronics. 14. The process of clause 64, any other suitable clause, or any combination of suitable clauses, wherein the device is a tube. 15. The process of clause 114, any other suitable clause, or any combination of suitable clauses, wherein the tube is sealed with a thermoseal. 16. The process of clause 114, any other suitable clause, or any combination of suitable clauses, wherein the tube is sealed at a first end of the tube, at a second end of the tube, or both. 17. The process of clause 116, any other suitable clause, or any combination of suitable clauses, wherein the first end of the tube is sealed with a thermoseal. 18. The process of clause 1 16, any other suitable clause, or any combination of suitable clauses, wherein the second end of the tube is sealed with a thcrmoscal. 19. The process of clause 116, any other suitable clause, or any combination of suitable clauses, wherein the first end of the tube is sealed with a thermoseal and the second end of the tube is sealed with a thermoseal. 0. The process of clause 64, any other suitable clause, or any combination of suitable clauses, wherein the device is a cannula. 1. The process of clause 64, any other suitable clause, or any combination of suitable clauses, wherein the device is a ring-shaped device. 2. The process of clause 64, any other suitable clause, or any combination of suitable clauses, wherein the device is an intravaginal delivery device. 3. A method of treating a disease in a subject using the device of any one of clauses 1 to 63, the method comprising the step of administering insulin to the subject via the device. 4. The method of clause 123, any other suitable clause, or any combination of suitable clauses, wherein the device is implanted in the subject. 5. The method of clause 124, any other suitable clause, or any combination of suitable clauses, wherein the device is subsequently removed from the subject. 6. The method of clause 123, any other suitable clause, or any combination of suitable clauses, wherein the disease is a glucose-responsive disease.
. The method of clause 123, any other suitable clause, or any combination of suitable clauses, wherein the disease is diabetes. . The method of clause 127, any other suitable clause, or any combination of suitable clauses, wherein the diabetes is Type 1 diabetes. . The method of clause 127, any other suitable clause, or any combination of suitable clauses, wherein the diabetes is Type 2 diabetes. . The method of clause 123, any other suitable clause, or any combination of suitable clauses, wherein the device is a tube. . The method of clause 123, any other suitable clause, or any combination of suitable clauses, wherein the device is a cannula. . The method of clause 123, any other suitable clause, or any combination of suitable clauses, wherein the device is a ring-shaped device. . The method of clause 123, any other suitable clause, or any combination of suitable clauses, wherein the device is an intravaginal delivery device. . A kit comprising ii) one or more hydrogel components, ii) an elastomer, and iii) instructions for producing a device. . The kit of clause 134, any other suitable clause, or any combination of suitable clauses, wherein the one or more hydrogel components comprise a glucose binding composition. . The kit of clause 135, any other suitable clause, or any combination of suitable clauses, wherein the glucose binding composition comprises phenylboronic acid (PBA), or wherein the glucose binding composition comprises 4-carboxy-3 -fluoro phenylboronic acid (FPBA), or wherein the glucose binding composition comprises PBA and FPBA.. The kit of clause 135, any other suitable clause, or any combination of suitable clauses, wherein the glucose binding composition consists essentially of PBA, or wherein the glucose binding composition consists essentially of FPBA, or wherein the glucose binding composition consists essentially of PBA and FPBA. . The kit of clause 135, any other suitable clause, or any combination of suitable clauses, wherein the glucose binding composition consists of PBA, or wherein the glucose binding composition consists of FPBA, or wherein the glucose binding composition consists of PBA and FPBA.
. The kit of clause 134, any other suitable clause, or any combination of suitable clauses, wherein the one or more hydrogel components comprise a crosslinker. . The kit of clause 139, any other suitable clause, or any combination of suitable clauses, wherein the crosslinker comprises N, N’-methylenebis(acrylamide) (MBAA).. The kit of clause 139, any other suitable clause, or any combination of suitable clauses, wherein the crosslinker consists essentially of MBAA. . The kit of clause 139, any other suitable clause, or any combination of suitable clauses, wherein the crosslinker consists of MBAA. . The kit of clause 134, any other suitable clause, or any combination of suitable clauses, wherein the one or more hydrogel components comprise a photo initiator.. The kit of clause 143, any other suitable clause, or any combination of suitable clauses, wherein the photo initiator comprises frgacure 2959 (1R2959). . The kit of clause 143, any other suitable clause, or any combination of suitable clauses, wherein the photo initiator consists essentially of IR2959. . The kit of clause 143, any other suitable clause, or any combination of suitable clauses, wherein the photo initiator consists of IR2959. . The kit of clause 134, any other suitable clause, or any combination of suitable clauses, wherein the elastomer is a polyurethane. . The kit of clause 147, any other suitable clause, or any combination of suitable clauses, wherein the polyurethane comprises a HydroMed D3 polyurethane. . The kit of clause 147, any other suitable clause, or any combination of suitable clauses, wherein the polyurethane consists essentially of a HydroMed D3 polyurethane.. The kit of clause 147, any other suitable clause, or any combination of suitable clauses, wherein the polyurethane consists of a HydroMed D3 polyurethane. . The kit of clause 147, any other suitable clause, or any combination of suitable clauses, wherein the polyurethane is selected from the group consisting of a HydroMed D7, D4, D3, DI, D6, D640 polyurethane, and combinations thereof. . The kit of clause 134, any other suitable clause, or any combination of suitable clauses, wherein the elastomer is a product of an elastomer solution. . The kit of clause 152, any other suitable clause, or any combination of suitable clauses, wherein the elastomer solution comprises a concentration of 18 wt%.
154. The kit of clause 152, any other suitable clause, or any combination of suitable clauses, wherein the elastomer solution comprises a concentration of 16-20 wt%.
155. The kit of clause 134, any other suitable clause, or any combination of suitable clauses, wherein the elastomer forms an elastomeric network.
156. The kit of clause 134, any other suitable clause, or any combination of suitable clauses, wherein the hydrogel components form a hydrogel.
157. The kit of clause 156, any other suitable clause, or any combination of suitable clauses, wherein the hydrogel is photocrosslinked.
158. The kit of clause 156, any other suitable clause, or any combination of suitable clauses, wherein the hydrogel is contained in an elastomeric network.
159. The kit of clause 158, any other suitable clause, or any combination of suitable clauses, wherein the hydrogel-elastomeric network forms an interpenetrating network.
160. The kit of clause 159, any other suitable clause, or any combination of suitable clauses, wherein the interpenetrating network is configured to release insulin.
161. The kit of clause 160, any other suitable clause, or any combination of suitable clauses, wherein the insulin can be released from any portion of the interpenetrating network.
162. The kit of clause 160, any other suitable clause, or any combination of suitable clauses, wherein the insulin can be released from one or more non-perforated portions of the interpenetrating network.
163. The kit of clause 134, any other suitable clause, or any combination of suitable clauses, wherein the device further comprises insulin.
164. The kit of clause 163, any other suitable clause, or any combination of suitable clauses, wherein the insulin is a fast acting insulin.
165. The kit of clause 163, any other suitable clause, or any combination of suitable clauses, wherein the insulin is a long acting insulin.
166. The kit of clause 163, any other suitable clause, or any combination of suitable clauses, wherein the insulin comprises a fast acting insulin, a long acting insulin, or a combination thereof.
167. The kit of clause 134, any other suitable clause, or any combination of suitable clauses, wherein the device is irradiated.
168. The kit of clause 167, any other suitable clause, or any combination of suitable clauses, wherein the irradiation is ultraviolet irradiation.
169. The kit of clause 134, any other suitable clause, or any combination of suitable clauses, wherein the device is configured to comprise a therapeutic agent.
170. The kit of clause 169, any other suitable clause, or any combination of suitable clauses, wherein the therapeutic agent is insulin.
171. The kit of clause 169, any other suitable clause, or any combination of suitable clauses, wherein the insulin is a fast acting insulin.
172. The kit of clause 169, any other suitable clause, or any combination of suitable clauses, wherein the insulin is a long acting insulin.
173. The kit of clause 172, any other suitable clause, or any combination of suitable clauses, wherein the insulin comprises a fast acting insulin, a long acting insulin, or a combination thereof.
174. The kit of clause 134, any other suitable clause, or any combination of suitable clauses, wherein the device is configured to contain a surfactant.
175. The kit of clause 174, any other suitable clause, or any combination of suitable clauses, wherein the surfactant is a non-ionic surfactant.
176. The kit of clause 174, any other suitable clause, or any combination of suitable clauses, wherein the surfactant comprises n-Octyl-P-d-glucoside.
177. The kit of clause 174, any other suitable clause, or any combination of suitable clauses, wherein the surfactant consists essentially of n-Octyl-P-d-glucoside.
178. The kit of clause 174, any other suitable clause, or any combination of suitable clauses, wherein the surfactant consists of n-Octyl-P-d-glucoside.
179. The kit of clause 134, any other suitable clause, or any combination of suitable clauses, wherein the device is configured to absorb glucose.
180. The kit of clause 179, any other suitable clause, or any combination of suitable clauses, wherein the device is a permeable device for the absorption of glucose.
181. The kit of clause 179, any other suitable clause, or any combination of suitable clauses, wherein the absorption occurs in a glucose responsive manner.
182. The kit of clause 179, any other suitable clause, or any combination of suitable clauses, wherein the absorption occurs under hypoglycemic conditions.
183. The kit of clause 179, any other suitable clause, or any combination of suitable clauses, wherein the absorption occurs under hyperglycemic conditions.
184. The kit of clause 134, any other suitable clause, or any combination of suitable clauses, wherein the device is implantable.
185. The kit of clause 184, any other suitable clause, or any combination of suitable clauses, wherein the implantable device is removable.
186. The kit of clause 134, any other suitable clause, or any combination of suitable clauses, wherein the device does not comprise a glucose-responsive plug.
187. The kit of clause 134, any other suitable clause, or any combination of suitable clauses, wherein the device is substantially free of electronics.
188. The kit of clause 134, any other suitable clause, or any combination of suitable clauses, wherein the device is a tube.
189. The kit of clause 188, any other suitable clause, or any combination of suitable clauses, wherein the tube is sealed with a thermoseal.
190. The kit of clause 188, any other suitable clause, or any combination of suitable clauses, wherein the tube is sealed at a first end of the tube, at a second end of the tube, or both.
191. The kit of clause 190, any other suitable clause, or any combination of suitable clauses, wherein the first end of the tube is sealed with a thermoseal.
192. The kit of clause 190, any other suitable clause, or any combination of suitable clauses, wherein the second end of the tube is sealed with a thermoseal.
193. The kit of clause 190, any other suitable clause, or any combination of suitable clauses, wherein the first end of the tube is sealed with a thermoseal and the second end of the tube is sealed with a thermoseal.
194. The kit of clause 134, any other suitable clause, or any combination of suitable clauses, wherein the device is a cannula.
195. The kit of clause 134, any other suitable clause, or any combination of suitable clauses, wherein the device is a ring-shaped device.
196. The kit of clause 134, any other suitable clause, or any combination of suitable clauses, wherein the device is an intravaginal delivery device.
[0044] In an illustrative aspect, a device is provided. The device comprises i) one or more hydrogel components and ii) an elastomer.
[0045] In an embodiment, the one or more hydrogel components comprise a glucose binding composition. In an embodiment, the glucose binding composition comprises phenylboronic acid (PBA). In an embodiment, the glucose binding composition consists essentially of PBA. In an embodiment, the glucose binding composition consists of PBA. In an embodiment, the glucose binding composition comprises 4-carboxy-3-fluorophenylboronic acid (FPBA). In an embodiment, the glucose binding composition consists essentially of FPBA. In an embodiment, the glucose binding composition consists of FPBA.
[0046] In an embodiment, the one or more hydrogel components comprise a crosslinker. In an embodiment, the crosslinker comprises N, N’-methylenebis(acrylamide) (MBAA). In an embodiment, the crosslinker consists essentially of MBAA. Tn an embodiment, the crosslinker consists of MBAA.
[0047] In an embodiment, the one or more hydrogel components comprise a photo initiator. In an embodiment, the photo initiator comprises Irgacure 2959 (IR2959). In an embodiment, the photo initiator consists essentially of IR2959. In an embodiment, the photo initiator consists of IR2959. [0048] In an embodiment, the elastomer is a polyurethane. In an embodiment, the polyurethane comprises a HydroMed D3 polyurethane. In an embodiment, the polyurethane consists essentially of a HydroMed D3 polyurethane. In an embodiment, the polyurethane consists of a HydroMed D3 polyurethane. In an embodiment, the polyurethane is selected from the group consisting of a HydroMed D7, D4, D3, DI, D6, D640 polyurethane, and combinations thereof.
[0049] In an embodiment, the elastomer is a product of an elastomer solution. In an embodiment, the elastomer solution comprises a concentration of 18 wt%. In an embodiment, the elastomer solution comprises a concentration of 16-20 wt%.
[0050] In an embodiment, the elastomer forms an elastomeric network. In an embodiment, the hydrogel components form a hydrogel. In an embodiment, the hydrogel is photocrosslinked. In an embodiment, the hydrogel is contained in an elastomeric network. In an embodiment, the hydrogel-elastomeric network forms an interpenetrating network. In an embodiment, the interpenetrating network is configured to release insulin. In an embodiment, the insulin can be released from any portion of the interpenetrating network. In an embodiment, the insulin can be released from one or more non-perforated portions of the interpenetrating network.
[0051] In an embodiment, the device further comprises insulin. In an embodiment, the insulin is a fast acting insulin. As used herein, the term "fast acting insulin" or "short acting insulin" refers to insulin analogues and/or insulin derivatives, wherein the insulin-mediated effect begins within 5 to 15 minutes and continues to be active for 3 to 4 hours. Examples of fast acting insulins include, but are not limited to, the following: (i). insulin aspart; (ii). insulin lispro and (iii). insulin glulisine. [0052] In an embodiment, the insulin is a long acting insulin. In an embodiment, the insulin comprises a fast acting insulin, a long acting insulin, or a combination thereof. As used herein, the term "long acting insulin" refers to insulin analogues and/or insulin derivatives, wherein the insulin-mediated effect begins within 0.5 to 2 hours and continues to be active for about or more than 24 hours. Examples of long acting insulins include, but are not limited to, the following: (i). insulin glargine; (ii). insulin detemir and (iii). insulin degludec.
[0053] Tn an embodiment, the device is irradiated. Tn an embodiment, the irradiation is ultraviolet irradiation.
[0054] In an embodiment, the device is configured to comprise a therapeutic agent. In an embodiment, the therapeutic agent is insulin. In an embodiment, the insulin is a fast acting insulin. In an embodiment, the insulin is a long acting insulin. In an embodiment, the insulin comprises a fast acting insulin, a long acting insulin, or a combination thereof.
[0055] In an embodiment, the device is configured to contain a surfactant. In an embodiment, the surfactant is a non-ionic surfactant. In an embodiment, the surfactant comprises n-Octyl-[3-d- glucoside. In an embodiment, the surfactant consists essentially of n-Octyl-β -d-glucoside. In an embodiment, the surfactant consists of n-Octyl-β-d-glucoside.
[0056] In an embodiment, the device is configured to absorb glucose. In an embodiment, the device is a permeable device for the absorption of glucose. In an embodiment, the absorption occurs in a glucose responsive manner. In an embodiment, the absorption occurs under hypoglycemic conditions. In an embodiment, the absorption occurs under hyperglycemic conditions.
[0057] In an embodiment, the device is implantable. In an embodiment, the implantable device is removable.
[0058] In an embodiment, the device does not comprise a glucose-responsive plug. In an embodiment, the device is substantially free of electronics.
[0059] In an embodiment, the device is a tube. In an embodiment, the tube is sealed with a thermoseal. In an embodiment, the tube is sealed at a first end of the tube, at a second end of the tube, or both. In an embodiment, the first end of the tube is sealed with a thermoseal. In an embodiment, the second end of the tube is sealed with a thermoseal. In an embodiment, the first end of the tube is sealed with a thermoseal and the second end of the tube is sealed with a thermoseal.
[0060] In an embodiment, the device is a cannula. In an embodiment, the device is a ring-shaped device. In an embodiment, the device is an intravaginal delivery device.
[0061] In an illustrative aspect, a process for producing a device is provided. The process comprises the steps of: a) combining one or more hydrogel components and a liquid composition comprising an elastomer to form a liquid combination, b) evaporating the liquid combination to form a hydrogel matrix, and c) irradiating the hydrogel matrix to form the device.
[0062] In an embodiment, the process is performed via a one-pot system. As used herein, a “one- pot” system can refer to a facile and efficient strategy for constructing a device compared to traditional stepwise methods and modifications for creation of devices.
[0063] In an embodiment, the device is an interpenetrating network. In an embodiment, the liquid composition comprising an elastomer is a solution. In an embodiment, the elastomer solution comprises a concentration of 18 wt%. In an embodiment, the elastomer solution comprises a concentration of 16-20 wt%.
[0064] In an embodiment, the process comprises use of a mold to form the device. In an embodiment, the liquid combination of step a) is placed in the mold. In an embodiment, step b) is performed on the liquid combination in the mold. In an embodiment, step c) is performed on the hydrogel matrix in the mold.
[0065] In an embodiment, the process further comprises a step d), wherein step d) comprises removing the device from the mold. In an embodiment, step d) comprises placing the device in water.
[0066] In an embodiment, the irradiation is ultraviolet irradiation. In an embodiment, the hydrogel matrix is photocrosslinked.
[0067] In an embodiment, the process further comprises a step of adding insulin to the device. In an embodiment, the insulin is a fast acting insulin. In an embodiment, the insulin is a long acting
insulin. In an embodiment, the insulin comprises a fast acting insulin, a long acting insulin, or a combination thereof.
[0068] In an embodiment, the process further comprises a step of adding a surfactant to the device. In an embodiment, the surfactant is a non-ionic surfactant. In an embodiment, the surfactant comprises n-Octyl-β-d-glucoside. In an embodiment, the surfactant consists essentially of n- Octyl-P-d-glucoside. In an embodiment, the surfactant consists of n-Octyl-β-d-glucoside.
[0069] In an embodiment, the one or more hydrogel components comprise a glucose binding composition. In an embodiment, the glucose binding composition comprises phenylboronic acid (PBA). In an embodiment, the glucose binding composition consists essentially of PBA. In an embodiment, the glucose binding composition consists of PBA. In an embodiment, the glucose binding composition comprises 4-carboxy-3-fluorophenylboronic acid (FPBA). In an embodiment, the glucose binding composition consists essentially of FPBA. In an embodiment, the glucose binding composition consists of FPBA.
[0070] In an embodiment, the one or more hydrogel components comprise a crosslinker. In an embodiment, the crosslinker comprises N, N’-methylenebis(acrylamide) (MBAA). In an embodiment, the crosslinker consists essentially of MBAA. In an embodiment, the crosslinker consists of MBAA.
[0071] In an embodiment, the one or more hydrogel components comprise a photo initiator. In an embodiment, the photo initiator comprises Irgacure 2959 (IR2959). In an embodiment, the photo initiator consists essentially of IR2959. In an embodiment, the photo initiator consists of IR2959. [0072] In an embodiment, the elastomer is a polyurethane. In an embodiment, the polyurethane comprises a HydroMed D3 polyurethane. In an embodiment, the polyurethane consists essentially of a HydroMed D3 polyurethane. In an embodiment, the polyurethane consists of a HydroMed D3 polyurethane. In an embodiment, the polyurethane is selected from the group consisting of a HydroMed D7, D4, D3, DI, D6, D640 polyurethane, and combinations thereof.
[0073] In an embodiment, the elastomer forms an elastomeric network.
[0074] In an embodiment, the device is configured to absorb glucose. In an embodiment, the device is a permeable device for the absorption of glucose. In an embodiment, the absorption occurs in a glucose responsive manner. In an embodiment, the absorption occurs under hypoglycemic conditions. In an embodiment, the absorption occurs under hyperglycemic conditions.
[0075] In an embodiment, the device is implantable. In an embodiment, the implantable device is removable.
[0076] In an embodiment, the device does not comprise a glucose-responsive plug. In an embodiment, the device is substantially free of electronics.
[0077] In an embodiment, the device is a tube. In an embodiment, the tube is sealed with a thermoseal. In an embodiment, the tube is sealed at a first end of the tube, at a second end of the tube, or both. In an embodiment, the first end of the tube is sealed with a thermoseal. In an embodiment, the second end of the tube is sealed with a thermoseal. In an embodiment, the first end of the tube is sealed with a thermoseal and the second end of the tube is sealed with a thermoseal.
[0078] In an embodiment, the device is a cannula. In an embodiment, the device is a ring-shaped device. Tn an embodiment, the device is an intravaginal delivery device.
[0079] In an illustrative aspect, a method of treating a disease in a subject using the device as described herein is provided. The method comprises the step of administering insulin to the subject via the device.
[0080] In an embodiment, the device is implanted in the subject. In an embodiment, the device is subsequently removed from the subject.
[0081] In an embodiment, the disease is a glucose-responsive disease. In an embodiment, the disease is diabetes. In an embodiment, the diabetes is Type 1 diabetes. In an embodiment, the diabetes is Type 2 diabetes.
[0082] In an embodiment, the device is a tube. In an embodiment, the device is a cannula. In an embodiment, the device is a ring-shaped device. In an embodiment, the device is an intravaginal delivery device.
[0083] In an illustrative aspect, a kit is provided. The kit comprises i) one or more hydrogel components, ii) an elastomer, and iii) instructions for producing a device.
[0084] In an embodiment, the one or more hydrogel components comprise a glucose binding composition. In an embodiment, the glucose binding composition comprises phenylboronic acid (PBA). In an embodiment, the glucose binding composition consists essentially of PBA. In an embodiment, the glucose binding composition consists of PBA. In an embodiment, the glucose binding composition comprises 4-carboxy-3-fluorophenylboronic acid (FPBA). In an
embodiment, the glucose binding composition consists essentially of FPBA. In an embodiment, the glucose binding composition consists of FPBA.
[0085] In an embodiment, the one or more hydrogel components comprise a crosslinker. In an embodiment, the crosslinker comprises N, N’-methylenebis(acrylamide) (MBAA). In an embodiment, the crosslinker consists essentially of MBAA. In an embodiment, the crosslinker consists of MBAA.
[0086] In an embodiment, the one or more hydrogel components comprise a photo initiator. In an embodiment, the photo initiator comprises Irgacure 2959 (IR2959). In an embodiment, the photo initiator consists essentially of IR2959. In an embodiment, the photo initiator consists of IR2959. [0087] In an embodiment, the elastomer is a polyurethane. In an embodiment, the polyurethane comprises a HydroMed D3 polyurethane. In an embodiment, the polyurethane consists essentially of a HydroMed D3 polyurethane. Tn an embodiment, the polyurethane consists of a HydroMed D3 polyurethane. In an embodiment, the polyurethane is selected from the group consisting of a HydroMed D7, D4, D3, DI, D6, D640 polyurethane, and combinations thereof.
[0088] In an embodiment, the elastomer is a product of an elastomer solution. In an embodiment, the elastomer solution comprises a concentration of 18 wt%. In an embodiment, the elastomer solution comprises a concentration of 16-20 wt%.
[0089] In an embodiment, the elastomer forms an elastomeric network.
[0090] In an embodiment, the hydrogel components form a hydrogel. In an embodiment, the hydrogel is photocrosslinked. In an embodiment, the hydrogel is contained in an elastomeric network. In an embodiment, the hydrogel-elastomeric network forms an interpenetrating network. In an embodiment, the interpenetrating network is configured to release insulin. In an embodiment, the insulin can be released from any portion of the interpenetrating network. In an embodiment, the insulin can be released from one or more non-perforated portions of the interpenetrating network.
[0091] In an embodiment, the device further comprises insulin. In an embodiment, the insulin is a fast acting insulin. In an embodiment, the insulin is a long acting insulin. In an embodiment, the insulin comprises a fast acting insulin, a long acting insulin, or a combination thereof.
[0092] In an embodiment, the device is irradiated. In an embodiment, the irradiation is ultraviolet irradiation.
[0093] In an embodiment, the device is configured to comprise a therapeutic agent. In an embodiment, the therapeutic agent is insulin. In an embodiment, the insulin is a fast acting insulin. In an embodiment, the insulin is a long acting insulin. In an embodiment, the insulin comprises a fast acting insulin, a long acting insulin, or a combination thereof.
[0094] In an embodiment, the device is configured to contain a surfactant. In an embodiment, the surfactant is a non-ionic surfactant. In an embodiment, the surfactant comprises n-Octyl-|3-d- glucoside. In an embodiment, the surfactant consists essentially of n-Octyl-β-d-glucoside. In an embodiment, the surfactant consists of n-Octyl-β-d-glucoside.
[0095] In an embodiment, the device is configured to absorb glucose. In an embodiment, the device is a permeable device for the absorption of glucose. In an embodiment, the absorption occurs in a glucose responsive manner. In an embodiment, the absorption occurs under hypoglycemic conditions. In an embodiment, the absorption occurs under hyperglycemic conditions.
[0096] In an embodiment, the device is implantable. In an embodiment, the implantable device is removable.
[0097] In an embodiment, the device does not comprise a glucose-responsive plug. In an embodiment, the device is substantially free of electronics.
[0098] In an embodiment, the device is a tube. In an embodiment, the tube is sealed with a thermoseal. In an embodiment, the tube is sealed at a first end of the tube, at a second end of the tube, or both. In an embodiment, the first end of the tube is sealed with a thermoseal. In an embodiment, the second end of the tube is sealed with a thermoseal. In an embodiment, the first end of the tube is sealed with a thermoseal and the second end of the tube is sealed with a thermoseal.
[0099] In an embodiment, the device is a cannula. In an embodiment, the device is a ring-shaped device. In an embodiment, the device is an intravaginal delivery device.
EXAMPLE 1
Exemplary Experimental Procedures
[0100] The instant example provides exemplary materials and methods utilized in Examples 2 to 10 as described herein.
MATERIALS:
[0101] The following chemicals and reagents were used in this study: Acrylamide (AAm), N, N’- methylenebis(acrylamide) (MBAA) and thionyl chloride purchased from Sigma-Aldrich (Saint Louis, U.S); Irgacure 2959 purchased from BASF (Florham Park, U.S.); HydroMedTM polyurethane (D3) purchased from AdvanSource Biomaterials (USA); 4-carboxy-3- fluorphenylboronic acid purchased from Combi-Blocks (San Diego, USA); PierceTM Coomassie Plus (Bradford) Assay Reagent and human recombinant insulin (catalog no. Al 138211) purchased from Thermofisher Scientific (Eugene, US); Ethylene diamine purchased from VWR International (Coming, US); and N-octyLglucopyranoside purchased from Krackeler Scientific, Inc (US).
METHODS:
[0102] Synthesis of 4-2-acrylamidoethy1carbamoyl-3-fluorophenyl boronic acid (AEC-FPBA) [0103] FPBA was synthesized according to a previously described method. Briefly, 4-carboxy-3- fluorophenylboronic acid (8 g) was added to a dried, three-neck round bottom flask and refluxed under a nitrogen atmosphere at 88 °C. Thionyl chloride (150 mL) was then added, and the suspension stirred and refluxed under a nitrogen atmosphere at 88 °C for one hour. After an hour, nitrogen was removed, and the reaction proceeded for 24 h at 88 °C to produce 4-carbonyl-3- fluorocyclohexyl boronic acid. The remaining thionyl chloride was evaporated, and the contents of the flask was resuspended in 60 mL of distilled tetrahydrofuran. The suspension was then added (dropwise) to cooled ethylene diamine (200 mL) in the presence of triethylamine (10 mL). The suspension was stirred in ice for 30 minutes and then at room temperature overnight. After overnight stirring, the ethylene diamine was evaporated, and the solution was acidified (pH 4) using IM HCL. A white precipitate byproduct was filtered out. The remaining solution was then concentrated and stored at 4 °C overnight. The collected crystals were dissolved in water and recrystallized twice to produce 4-aminoethylcarbamoyl-3-fluorophenylboronic acid (AECPBA). AECPBA crystals were collected and dissolved in 150 mL of sodium bicarbonate (100 mM, pH 10) and 62.5 mL of 1 M NaOH in an ice cooled bath. Acryloyl chloride (5 mL) was then added dropwise. The mixture was stirred for 30 minutes in the ice bath, and then at room temperature for 5-6 hours. After stirring, the solution was concentrated and acidified (pH 4) using IM HC1. The solution was once again concentrated and stored at -20 °C overnight to produce a white crystalline product (FPBA).
[0104] Preparation of elastomer material:
[0105] A commercially available polyurethane (PU, HydroMed D3) was dissolved in a 95:5 mixture of ethanol (EtOH) and Mili-Q water to obtain an 18 w/v% solution. Films and tubes were prepared using a solution-casting method at room temperature (Figure 2A). After evaporation of the solvent mixture, molds were immersed in water, allowing the material to crosslink, swell, and release from the molds. The prepared tubes or films were then stored in water for a subsequent three days, with water changed daily. Rather than fully cylindrical cannulas, conical molds were selected to minimize resistance during the needle-assisted insertion process of the core-shell cannulas.
[0106] Preparation of hydrogel-elastomer materials
[0107] To introduce glucose sensitivity to the system, FPBA monomers (6 w/v%), MBAA (0.01 w/v%), and 1R2959 (0.4 w/v%) were added to PU-D3 solutions as the glucose binding moiety, crosslinkcr, and initiator, respectively. Given the hydrophobic nature of PU-D3 and FPBA, AAm (2 w/v%) was added to the solution to facilitate mixing and incorporation of the hydrogel material. Contents were stirred until the pre-gel solution became clear. Solutions were then sonicated for 30 minutes at room temperature using a VWR Ultrasonic Cleaner for degassing purposes. Films and tubes were prepared using a solution-casting method at room temperature (Figure 2A). After evaporation of the solvent mixture under ambient room temperature conditions, UV- polymerization of the hydrogel material was triggered using an Omnicare UV for 300 seconds. After UV treatment, the elastomer-hydrogel thin films/tubes were immersed in DI water for three days to ensure full swelling and crosslinking of the elastomer material. Unreacted monomers were removed through daily water changes.
[0108] Characterization of mechanical properties
[0109] Mechanical property tests of the hybrid materials were carried out in air at room temperature. Tensile strength tests were carried out using an Instron 4680 mechanical testing instrument with a grip-to-grip speed of 20 mm/min.
[0110] Preparation of insulin stock solution
[0111] Insulin was prepared according to a previously described protocol. Briefly, insulin (25 mg) and n-octyl-glucopyranoside (3.65 mg) were dissolved in 0.1 M NaOH aqueous solution (600 pL). 4-(2-hydroxyethyl)-l -piperazineethanesulfonic acid) (HEPES) (12.6 mg) was then added, and the
volume was brought to 1 mL by a slow addition of 0.1 M HCL. A transparent solution was obtained at ~ pH 7.
[0112] Formation of cannulas
[0113] Cannulas were formed using a solvent casting method. Ends-sealed cannulas were thermosealed on one end, filled with insulin, and thermo- sealed on the filling end to create a closed device. Transcutaneous, externally refillable cannulas were formed by adding a silicone tube (SMI Silicone Tubing Tube 0.025” X 0.047” 50D CL) to an open end of the solvent-casted cannula. The silicone tube was secured in place with the addition of UV glue. The other end of the cannula (not attached to the silicone tube) was then sealed via thermo-sealing. Then, the silicone-end of the cannula was slipped on to the 22-gauge adapter of the mouse VAB™ button (INSTECH), creating the final, ready-to-use product.
[01 14] 3D printing of insulin reservoirs
[0115] 3D CAD models of the insulin reservoirs were designed using 3D modeling software (Autodesk 3ds Max). The reservoirs were printed on a 3D printer (Form 2, Formlabs), using clear resin material (Formlabs). Samples were washed in 2-propanol for 15 minutes, and cured under UV at 60°C for 60 min.
[0116] Construction of core- shell cannula
[0117] Core-shell cannulas were fabricated as follows. A silicone tube (SMI Silicone Tubing 0.025” X 0.047” 50 D CL) was then fitted inside the lumen of the glucose-responsive and control cannulas. The two layers of the cannula were glued together (UV glue, J-B Weld) at the distal end of the cannula to create a sealed outer lumen. The combined, core-shell cannula was then fitted to the bottom opening of the insulin reservoir and sealed in place with UV glue. The rest of the openings on the insulin reservoir were sealed with PDMS to create a rubber stopper to keep contents inside the reservoir aseptic while allowing for refilling of the reservoir via needle insertion.
EXAMPLE 2
Exemplary Experimental Procedures
[0118] The instant example provides exemplary materials and methods utilized in Examples 3 to 10 as described herein.
[0119] Animal Studies
[0120] All animal experiments were approved by the Cornell University Institutional Animal Care and Use Committee. The in vivo efficacy of the glucose-responsive insulin delivery devices was evaluated on streptozotocin (STZ)-induced adult diabetic mice (male C57BL/6J mice; 8 weeks old; The Jackson Laboratory). Typically, after overnight fasting, mice were intraperitoneally injected with STZ (140 mg/kg). After 1 week, mice with a fasting blood glucose level higher than 300 mg/dL were confirmed as type 1 diabetic mice and used for further experiments.
[0121] Blood glucose reduction potential studies for insulin stability
[0122] The stability of insulin in the devices was evaluated using a blood glucose reduction protocol. Devices were first prepared as described above and stored under static conditions at either 4°C or 37°C to evaluate long term storage and in vivo temperature effects of the enclosed insulin, respectively. At pre-determined time points, insulin from the devices was extracted and subsequently subcutaneously injected into diabetic mice at a set dose of 0.05 mg. The blood glucose of the mice (as measured with a Clarity GL2Plus glucose meter) was monitored prior-to and one hour after the insulin injection. The reduction in BGL was attributed to the physiological action of the injected insulin. A freshly prepared device (‘As Prepared’) indicates a device that was made and immediately had the insulin extracted after thermo- sealing; a freshly made device was used to evaluate the effects of the fabrication procedure on the therapeutic potential of insulin. The BGL reduction of a freshly prepared insulin solution (or native insulin solution) was used as control.
[0123] Glucose absorption study with glucometer
[0124] Membranes (1cm x 1cm x 0.5 cm) were placed in glass vials with 10 mL phosphate buffer saline (PBS, pH 7.4) containing different glucose concentrations (100, 200, or 400 mg/dL). The vials were incubated at room temperature, and the glucose concentration of the supernatant was monitored at timed intervals using a glucose meter (Clarity BG 1000, CD-BG1). The concentration of the solution was calculated using an established standard curve.
[0125] Glucose absorption study with glucose oxidase kit
[0126] Glucose absorption was determined following the outlined protocol for the Glucose Oxidase (GO) Kit (Sigma- Aldrich, catalog no. GAGO20). Briefly, membranes (1cm x 1cm x 0.5 cm) were placed in glass vials containing 10 mL PBS (pH 7.4) and different glucose concentrations (100, 200, or 400 mg/dL). The vials were incubated at room temperature. At timed intervals, a 1 mL supernatant solution from each sample was collected and pipetted into a test tube. Assay
Reagent (2mL, GO kit) was added to the collected supernatant, an incubated at 37°C for 30 minutes. The reaction was stopped after 30 minutes by the addition of 2 mL of 6M H2SO4. The absorbance of each sample was measured at 540 nm using UV/Vis spectrophotometry (Beckman Coulter DU 730). The concentration of the solution was calculated using an established standard curve.
[0127] In vitro insulin release study
[0128] Insulin release was determined as a function of glucose concentration over time. Devices loaded with insulin (1.25 mg) were placed in centrifuge tubes containing the release medium (2 mL of PBS, pH 7.4) at different concentrations of glucose (0, 100, or 400 mg/dL). Samples were thermo-sealed and incubated at 37°C, 70 revolutions per minute (RPM) for the duration of the experiment. At timed intervals, a clear supernatant (50 pL) was collected and added to Coomassie blue (300 pL); 50 pL of fresh release medium was added to each centrifuge tube following collection of the supernatant. Absorbance of the solution was measured at 595 nm, with the concentration calibrated using an established standard curve. The glucose-responsiveness of the devices (R) was calculated as the ratio of insulin release under hyperglycemic glucose (400 mg/dL) to normal glucose (100 mg/dL).
[0129] Blood glucose control in TID diabetic mice
[0130] Diabetic mice were allocated to different groups and were treated with subcutaneously injected native insulin or with implanted devices containing 1.5 mg of human recombinant insulin (100 pL of a 15 mg/mL solution). FPBA devices were used as test groups, and PU devices were used as control devices. The BGLs were monitored using a Clarity GL2Plus glucose meter.
[0131] Cy5-Insulin and in vivo imaging
[0132] 30 mg of human recombinant insulin (catalog no. A11382II) were dissolved in 10 mM sodium carbonate buffer (30 mL, pH ~8). 150 pL of Cy5 (5 mg/mL DMSO) was added to the mixture and stirred overnight. The contents were then dialyzed against DI H2O (3x 2L). The resultant solution was lyophilized to obtain Cy5-labeled insulin. The fluorescently labeled insulin was imaged using an IVIS-Spectrum optical imager.
[0133] Intraperitoneal glucose tolerance test
[0134] The intraperitoneal glucose tolerance test (IPGTT) was performed to confirm the in vivo glucose-responsive nature of the implanted devices. Prior to the experiment, mice were fasted overnight and then allocated to different groups and treated with subcutaneously implanted devices
(e.g. FPBA or PU devices). Once normoglycemia (BGL: 100 mg/dL < x 200 mg/dL) was achieved approximately 1 hour after device implantation, a glucose solution was injected intraperitoneally into all mice at a dose of 1.5 g/kg. Glucose levels were then monitored at specific time points to assess the return to normoglycemia following the glucose injection. The IPGTT was performed on healthy, non-diabetic mice as control.
[0135] Serum Insulin Level Measurements
[0136] To measure the serum insulin concentration of the mice, 50 |aL were drawn from the submandibular vein of the mice at indicated time points. The samples were stored at -20°C until assayed. The plasma insulin concentration was then measured using a Human Insulin ELISA kit (ALPCO).
[0137] Histological Analysis
[0138] Skin samples with glucose-responsive or control devices were fixed with neutral buffered formalin and embedded in paraffin. Sections were subsequently stained with hematoxylin and eosin and Masson’s Trichrome.
[0139] Statistical Analysis
[0140] All data shown are means ± standard deviations. Student’s t-tests or ANOVA with Turkey post hoc tests were used to analyze the difference between two or more groups, respectively. Statistical significance was evaluated as *, **, ***, ****, and ns, which represented p-valucs < 0.05, < 0.01, < 0.001, < 0.0001, and > 0.05, respectively.
EXAMPLE 3
Design and fabrication of elastomer-hydrogel hybrid materials
[0141] In the instant example, the design and fabrication of elastomer-hydrogel hybrid materials are described.
[0142] Hydrogels have been extensively explored for precise drug delivery purposes given their ability to respond to a stimulus (e.g., glucose) via physiological changes to their network to release enclosed cargo (e.g., insulin). Several different hydrogel materials functionalized with glucose responsive moieties have been successfully shown to mitigate hyperglycemia through stimuli- responsive insulin release. Unfortunately, clinical translation remains poor, as many hydrogels suffer from weak mechanical properties, which are further exacerbated by the harsh in vivo milieu. This raises significant concerns in the case of device failure or medical complications, as complete
retrieval of hydrogel devices after implantation becomes nearly impossible if the hydrogel matrix has been compromised. Not to mention that retrievability is a crucial factor associated with the regulatory approval processes.
[0143] A one-pot solvent exchange method to produce an elastomer-hydrogel interpenetrating network material with robust mechanical properties capable of forming implantable devices is provided (Figures 1A, IB, 2A). The fabrication process begins by incorporating and dissolving the hydrogel network components — a glucose binding moiety (FPBA), crosslinker (MBAA), and photo-initiator (IR2959) — to a pre-prepared elastomer (PU-D3) solution. Then, a solvent-casting method is employed in which a mold is selected for the hybrid material to obtain the final desired geometry and shape of the implantable device (Figure 2A). The solvent is then evaporated at ambient temperature before UV treatment using an Omicare UV. Under UV irradiation, the hydrogel matrix is photo-crosslinked to entrap the hydrogel within the elastomer network, thereby forming an interpenetrating network material (Figure 1A). After immersing the cross-linked material in water, the hybrid material swells off from the fabrication mold, producing a uniform and ready-to-use final cannula (Figure 2A).
[0144] The simple fabrication process is conducive to scale-up or scale-down requirements, as the final form of the device is contingent upon the mold selected for fabrication (Figure 2B). While we explored the application of this material for glucose-responsive insulin delivery, functionality of the material is contingent on the monomers used in the hydrogel component. As such, one could functionalize the material with other ‘responsive’ properties (i.e., pH-responsiveness, temperature sensitivity, etc.) so long as the selected hydrogel monomer(s) are water soluble and form a network through UV irradiation. Such materials might have interesting stimuli-responsive therapeutic applications.
[0145] Importantly, the hybrid material responds to changes in glucose concentrations rapidly due to the incorporation of FPBA or PBA (see, e.g., Figure IB). As mentioned above, under hyperglycemic conditions, glucose can reversibility and dynamically bind to phenylboronic acids, rendering the phenylboronic acid more hydrophilic while increasing the negative charge density of the system. This increase in hydrophilic character increases the permeability of the carrier material to release insulin in a glucose-responsive fashion. Without being bound by any theory, the process is demonstrated as reversible, with insulin release “turned-off’ under hypoglycemic conditions. Despite the inherently high pKa of most phenylboronic acids, the chemical structure
of FPBA was selected and synthesized such that monomer may be incorporated into the final material while undergoing the aforementioned glucose responsive swelling-behavior under physiologically relevant conditions. This diffusion-based insulin release mechanism provides a simple and artificial method to replicate pancreatic function as compared to more complicated fabrication, storage, and algorithm-controlled sensing mechanisms of enzyme-based “smartinsulin” delivery platforms.
EXAMPLE 4
Preparation of devices and stability of insulin complexes within devices
[0146] In the instant example, the potential of the hybrid material to serve as a glucose-responsive insulin delivery device is evaluated.
[0147] Once fabricated, the devices can be loaded with insulin to form an insulin delivery device. Importantly, the device responds to changes in glucose concentrations rapidly due to the incorporation of phenylboronic acid (PBA). Under hyperglycemic conditions, glucose can reversibility and dynamically bind to phenylboronic acids, rendering the phenylboronic acid more hydrophilic while increasing the negative charge density of the system. This increase in hydrophilic character increases the permeability of the carrier material, to release insulin in a glucose-responsive fashion (Figure IB). The process is reversible, with insulin release shut off under hypoglycemic conditions.
[0148] Prepared tubes may be thermo-sealed at one end, subsequently loaded with an insulin solution, followed by thermo-sealing of the filling end to create a closed device. The simple fabrication process is conducive to scale-up or scale-down requirements, as the final form of the device is contingent upon the mold selected for fabrication (Figure 2B). Likewise, the volume and concentration of insulin loaded within the devices can be user-defined, thereby facilitating insulin loading within the devices at a larger capacity than other non-reservoir-based “smart insulin” devices that have been developed such as microneedle patches or micro/nanoparticles. Additionally, unlike other reservoir-based devices, the mechanical robustness of the hybrid material is such that the entire surface of the device is composed of the glucose-sensing material, consequently providing a continuous and large surface area for glucose-binding without the need for harsh, multi-step surface modification procedures or additional mechanically reinforcing
components within the device. Ideally, such a continuous glucose-sensing surface should facilitate more rapid and robust glucose-detection and subsequent insulin release.
[0149] To quantify the mechanical robustness of the hydrogel-elastomer material, the tensile strength of the hybrid material as a function of hydrogel concentration was measured (Figures 3B, 3C, 4A, 4B, 4C). The concentration of the elastomer (Hydromed, D3) was fixed at 12.5% (w/v%) for these mechanical characterization tests. This was because preliminary tensile-stress test of the pure elastomer material (polyurethane or PU) showed that maintaining the concentration of material between 10-30% (w/v%) provided an ideal balance between mechanical strength (Figures 20A, 20B) and viscosity conducive to forming cannulas through the dip-coating fabrication procedure.
[0150] Without being bound by any theory, the mechanical strength of the hybrid material may be enhanced compared to pure hydrogel films (Figure 3B) and may demonstrate remarkable recoverability from deformation under cyclic loading (Figure 3C). While the energy dissipated in the second cycle was observed to be lower than that of the first cycle, it remained approximately constant for subsequent cycles. It is possible that rearrangements in the interpenetrating network structure during the first cycle contributed to this phenomenon, and this reconfiguration contributes to the material’s ability to maintain elasticity and strength under subsequent cyclic loading. Advantageously, these features contributed to the material’s ease of handling compared to its pure hydrogel counterpart when formed into a cannula (Figure 3A). While the elastomer concentration was fixed at 12.5 w/v%, the mechanical properties of the final hybrid material were broadly subject to the amount of hydrogel in the system. It may be postulated that incorporating a higher concentration of the hydrogel component dilutes the density of the original elastomer network, thereby softening the material (Figure 4C) and compromising the overall tensile strength of the final product (Figures 4 A, 4B). Moreover, incorporating a higher concentration of hydrogel into the final constructs increases the overall water content and hence permeability of the construct (Table 1). Therefore, a balance between hydrogel content and the mechanical properties of the materials should be considered for case-specific scenarios. For the instant application, the final concentrations of hydrogel (8% w/v%) and elastomer (18% w/v%) were selected for an optimal balance of mechanical strength and FPB A content for glucose responsiveness as an insulin infusion cannula.
[0151] Table 1. Water content of the hybrid material as a function of hydrogel concentration.
[0152] Given the intended purpose of these devices as insulin delivery vectors, it was crucial to test the stability of insulin solutions enclosed within the hybrid material (Figures 5A-5C). It has been shown that highly concentrated insulin solutions can quickly undergo aggregation (e.g., fibrillation) when contacting hydrophobic surfaces. This was of concern given both the high insulin concentration loaded in the cannulas and the hydrophobic nature of the hybrid-material, as insulin aggregation could potentially block the pores of the glucose-responsive membrane, leading to poor insulin release or even the release of non-active insulin. To prevent insulin aggregation, a previously established strategy was followed to stabilize insulin through the addition of the nonionic surfactant, n-octyl-|3-glucopyranoside. Incorporating the surfactant permitted insulin to be stored stability within the devices at 4 °C for one month and at 37 °C for one week (Figures 5B, 5C). Specifically, the blood glucose reducing potential of a freshly prepared insulin solution was comparable to the reducing potential of insulin stored in the device, demonstrating that neither the fabrication procedure nor the long-term storage of insulin within the devices affected the insulin’s therapeutic potential (Figure 5A).
EXAMPLE 5
In vitro evaluation of glucose-responsive performance
[0153] In the instant example, the in vitro evaluation of glucose-responsive performance was evaluated.
[0154] Since the diffusion-based insulin release from the cannulas was theorized to occur from the volumetric swelling of the matrix caused by the complexation of glucose to FPBA monomers, whether the hybrid material was capable of binding to glucose after fabrication was first investigated. To do so, sheets of the material were immersed in PBS buffers (pH 7.4) containing different clinically relevant concentrations of glucose. Results were consistent for all membranes able to absorb glucose (Figures 6B, 6C). However, only membranes containing FPBA, the glucose- binding element, absorbed glucose in a glucose responsive fashion, with more glucose binding occurring under hyperglycemic conditions than in hypoglycemic conditions (p < 0.05) (Figure 6C).
[0155] Glucose absorption measured via both a glucometer and a glucose oxidase (GOx) assay supported the glucose concentration-dependent absorption of FPBA membranes (Figure 6D). Accompanying increases in permeability evaluated by changes in water content were also observed in the membranes, with only membranes containing the glucose-binding element showing increased swelling in response to rising glucose concentrations, although the response was only statistically significant under hyperglycemic conditions (Figures 21 A, 2 IB). Without being bound by any theory, these findings may demonstrate that the incorporation of FPBA may endow the hydrogel-elastomer material with glucose-responsive properties.
[0156] Next, the insulin release potential from the devices upon variations of glucose concentrations was assessed. Thermo-sealed, ends-closed cannulas loaded with insulin (1.25 mg) were placed in centrifuge tubes containing the release medium (2 mL of PBS, pH 7.4) at different glucose concentrations (0, 100, or 400 mg/dL) and incubated at 37 °C, RPM 70. While the rate of insulin release (R) was variable based on the concentration of insulin loaded in the cannulas (Figures 22A, 22B, 22C, 22D, Table 2), generally, higher rates of insulin release were obtained at hyperglycemic (400 mg/dL) glucose levels than normoglycemic levels (100 mg/dL) for FPBA cannulas (Figures 7B, 7G, 7H). Moreover, the insulin release profile of the FPBA cannula exhibited a typical pulsatile pattern when glucose concentrations were alternated between normal (100 mg/dL) and hyperglycemic levels (400 mg/dL) for several cycles, supporting the on-off release function of the cannula (Figure 71). In contrast, control PU devices demonstrated negligible glucose-responsive insulin release and did not support pulsatile insulin delivery (Figures 7A, 7D, 7E, 7F). Collectively, without being bound by any theory, these results may substantiate that the ends-sealed cannulas made of the hybrid material supported glucose-mediated insulin release in vitro under physiologically relevant parameters, with the fast insulin release kinetics showing great potential to regulate BGLS in real time effectively.
EXAMPLE 6
In vivo evaluation of glucose-responsive performance
[0158] In the instant example, the in vivo therapeutic efficacy of the devices implanted in type 1 diabetic mice models induced by streptozotocin (STZ) (Figures 8A, 8B).
[0159] The diabetic mice were assigned to be treated with either a subcutaneous injection of PBS or insulin (0.05 mg) or with a subcutaneous implantation of an insulin reservoir device either with the glucose responsive properties (PBA device) or the pure elastomer control (PU), both at a dose of 1.5 mg of insulin. The blood glucose levels of all treated groups decreased to below 200 mg/dL within one hour of receiving insulin, indicating the rapid blood sugar reducing capacities of insulin-based treatments (Figure 8C). However, mice treated with an insulin injection showed only transient glycemic control, with the mice returning to hyperglycemic BGLs within two-to-thrcc hours after receiving the insulin injection (Figure 8F). In contrast, mice with insulin reservoirs showed prolonged glycemic control, on average lasting for three days (Figure 8C). Importantly however, when comparing the glucose-responsive reservoirs (FPBA) and control reservoirs, FPBA-based devices were shown both to prevent hypoglycemic episodes, which remains one of the outstanding challenges of many “smart” insulin delivery technologies, and maintained glucose levels within the normal range (100 mg/dL < x < 200 mg/dL) for approximately 72 hours before the mice returned to hyperglycemic BGLS (Figures 8D, 8G). This BGL regulation was much longer and more robust than either insulin injections or control (PU) reservoir devices, as mice in the PU group experienced severe hypoglycemia from unregulated insulin delivery for the duration of the experiment, gravely diminishing their survival (Figure 8E). Live imaging using Cy5-labeled insulin further confirmed the prolonged delivery of insulin from reservoir devices compared to injected insulin (Figures 9D, 9E, 9F). “Failure” or the return to hyperglycemic BGLs likewise seemed to occur from near complete insulin release from devices, as evidenced by diminished average relative fluorescence intensity with increasing BGLs (Figure 10).
[0160] Next, intraperitoneal glucose tolerance tests (IPGTTs) were performed to assess the in vivo glucose-responsive performance of the cannulas (Figures 9A, 9B, 9C). Blood glucose peaks were observed for healthy mice and mice treated with FPBA cannulas (Figure 9A). Notably, serum insulin levels increased in response to the acute glucose bolus (Figure 9C). PU devices on the other hand, experienced severe hypoglycemia (e.g., no glycemic peak), and only the healthy mice and FPBA-treated mice reestablished normoglycemia in a brief period (Figure 9A). This fast in vivo glucose-responsive insulin release kinetics of the FPBA devices is essential for maintaining normoglycemia when facing glucose challenges. Encouragingly, without being bound by any theory, these data may indicate the potential of FPBA devices at robustly controlling glycemic levels through in vivo glucose-responsive insulin delivery behaviors.
[0161] Importantly, one-week post-implantation, the ends-closed cannulas could be completely retrieved without tissue adhesion or gross deformation (Figure 1 1C). H&E and Masson Trichrome staining showed a non-uniform, but mostly thin layer of cells deposited on the cannula surface (Figure 11B, 12, 13A, 13B, 13C). Without being bound by any theory, it may be possible that a combination of the local trauma caused by cannula insertion, active release of insulin, and the hydrophobic nature of the material used to fabricate the cannulas contributed to the areas of higher cell deposition seen in certain regions (Figure 13A, 13B, 13C). It is important to note, however, that the incorporation of the HydroMed™ polyurethane layer within the material makes the devices susceptible to ethanol-induced degradation. This may make the devices vulnerable to degradation during histology fixation steps, given that ethanol is a commonly used coagulant fixative. To minimize dissolution, prior to sample fixing in formalin, freshly explanted devices were embedded in HistoGel™. Generally, incorporation of the HistoGel™ preserved most of the samples for a preliminary analysis of the fibrotic response against the implanted devices (Figure 1 IB). Although the cannulas may be used for short-term use, further investigation into fibrosisreducing materials are warranted to minimize interference between the cannula surface and the environmental interstitial fluid to maximize the glucose-responsive insulin release performance of the cannula.
EXAMPLE 7
Core-Shell Cannula
[0162] In the instant example, the design and fabrication of the core-shell cannula are examined.
[0163] Currently, the majority of type 1 diabetes (T1D) patients practice basal-bolus dosing, that is, administering a long-lasting insulin analogue at regular intervals (the basal dose), and a fastacting insulin before meals (the bolus dose), adjusted according to meal composition. To support this insulin regimen, a core-shell cannula that attaches to an insulin reservoir was designed; the previously described glucose-responsive membrane is wrapped around an inner silicone lumen to allow this outer layer to act as a glucose-responsive reservoir for controlled basal (e.g., long-term) insulin release while the inner, open-ended lumen allows for rapid infusions of large quantities of insulin, akin to bolus (e.g., mealtime) insulin delivery. Without being bound by any theory, this new cannula/device design may support glucose-responsive basal insulin infusion and bolus insulin delivery when evaluated in vitro under physiologically relevant glucose-concentrations.
[0164] Glucose responsive insulin cannula:
[0165] Commercially available cannulas for home insulin delivery are made of stainless steel or flexible soft polymers. Insulin flows from the distal tip of the cannula when a small basal dose or a larger meal- time bolus is delivered. A pool of insulin forms under the skin which is taken up into the blood and lymphatic systems. Slowed absorption and insulin degradation due to inflammatory cell enzymatic activity contribute to decreased insulin effectiveness. Similarly, unexpected hyperglycemia can also occur due to a blockage of insulin flow through the cannula or tubing, which are thought to underly approximately 30% of decisions to change an insulin infusion set during clinical trials. When the cannula experiences an occlusion or kink, it is inferred based on hyperglycemia or increased resistance to insulin dosage sensed by the pump prompting an alarm on the pump. Insulin infusion sets are to be changed every 2-3 days according to FDA guidance. Even within a 2-to-3-day wear period, unexplained hyperglycemia occurs sometimes due to cannula non-function. The glucose-responsive material may significantly impact the way insulin dependent diabetes is treated with constant subcutaneous infusion. As a cannula, the material may improve absorption of insulin by distributing the bolus of liquid in the subcutaneous tissue, and the glucose-responsive changes in permeability of the cannula will reduce insulin adsorption to the cannula. The material may allow insulin to percolate to any area where the tissue will expand, and this flow could continue despite closure of the main lumen, due to permeability along the wall of the cannula. Extended functional wear may result from fibrosis reducing intrinsic properties of the novel polymer. Without being bound by any theory, fewer malfunctions and
reduced infusion site changes may reduce stress on diabetic patients and caregivers, improving the sense of wellbeing, improving overall health.
[0166] Design and fabrication of the core-shell cannula:
[0167] To combine the function of a commercially available CGM (glucose detection) and insulin pump (insulin infusion) into a single device, the previously developed glucose-responsive material to form a core-shell cannula was utilized. In this design, the entire outer shell of the cannula serves as a glucose-responsive module to support routine (basal) insulin needs by regulating changes in insulin infusion based on the synergistic net charge shift of the FPB A polymeric network at varying glucose concentrations (Figures 14A, 14B). Under hyperglycemic conditions, the increase in binding of glucose to FPBA units may cause an increase in the negative charge density inside the hydrogel network of the hybrid hydrogel-elastomer material, causing insulin release by electrostatic repulsion (Figure IB). Unlike commercially available cannulas that only release insulin from the distal end, the entirety of the core-shell wall is permeable and participates in the diffusion based, glucose-binding insulin release process (Figure 15). Such a design can provide multiple pathways for the infused insulin to be delivered in the case of kinking and subsequent occlusion (or partial occlusion), a leading cause of failure for cannulas in many tethered and patchpump insulin delivery technologies. Without being bound by any theory, this may likewise reduce the need for premature catheter changes due to clogging, which may substantially contribute to patient’s well-being.
[0168] On the other hand, the inner open-ended silicone core allows for rapid injections of large quantities of insulin to support mealtime (bolus) insulin requirements (Figure 14A). The inner core also allows for an introducing needle to pierce through the lumen of the prototype for direct subcutaneous insertion without disturbing the reservoir-function of the glucose-responsive layer (Figure 14G). This may eliminate the need of implantation required of the previous iterations of the cannula (e.g., the ends-sealed and the transcutaneous, externally refillable cannula). Moreover, given that the phenylboronic acid-based (e.g., FPBA) glucose sensing mechanism differs from conventional glucose-oxidase based CGMs, it can be postulated that this design may also minimize (and even potentially eliminate) concerns of interference to glucose-sensing from preservatives used in insulin formulations.
[0169] Consequently, to create a fully synthetic artificial pancreas (AP) device, the core-shell, glucose-responsive cannula was attached to an insulin reservoir (Figure 14B). The outer lumen of
the cannula is fed the insulin from the reservoir to support basal insulin needs, while the inner lumen remains open to allow for rapid infusion of larger insulin quantities needed during bolus insulin infusion (Figures 14C, 14D). The two port-design on the insulin reservoir facilitates the distinction between the two functions of the cannula, as one port directly connects to the insulin reservoir for external refilling of the reservoir, while the other connects to the inner core of the cannula for bolus infusions (Figures 14E, 14F). Collectively, this design may facilitate a more user-friendly insertion process of the cannula while supporting both basal and bolus insulin delivery in an electronics and software-free manner.
EXAMPLE 8
In vitro Evaluation of the Core-Shell Cannula
[0170] In the instant example, the in vitro evaluation of glucose-responsive performance of the core- shell cannula was evaluated.
[0171] After forming the devices, the suitability of the core-shell cannula prototype to support insulin delivery was explored. To assess the insulin release profiles from the cannulas, insulin reservoirs were loaded with -200 pL of insulin (10 mg/mL), and then placed the insulin-filled devices in release mediums with different physiologically relevant glucose concentrations (e.g., 0, 100, or 400 mg/dL). Only core-shell devices containing FPBA (e.g., the glucose-binding monomer) showed glucose-dependent release behavior while control, PU-based core-shell cannulas showed negligible glucose-responsive insulin release, instead releasing similar quantities of insulin regardless of the glucose-concentration in the release medium (Figures 16A, 16B). While the insulin release rates were lower than that of fully scaled, cnds-closcd cannulas, even when loading a much lower, commercially relevant concentration of insulin in the reservoir (U100 = 3.47 mg/dL), the FPBA core-shell cannulas supported glucose-dependent basal insulin release (Figures 17A, 17B, Table 3). These basal insulin release rates are comparable to lower-end basal rates required by T1D patients using insulin pumps (Figure 17C).
[0172] Table 3. Quantitative insulin release rates in Units (U) of insulin per hours (h) from cannulas
[0173] Of note however, is the delay in response between the release rates in low (100 mg/dL) and high (400 mg/dL) glucose concentrations for the FPBA devices; only after four hours of release was a statistically significant difference observed across all glucose concentrations (Figure 16B). Although a pulsatile release profile was exhibited for the FPBA core-shell cannulas when alternating incubating the devices in low (100 mg/dL) and high (400 mg/dL) glucose concentrations, the results were not statistically significant, even when extending incubation times from 15 minutes to 30 minutes (Figure 16C). Without being bound by any theory, it is plausible that the reduction in loading volume compared to ends-sealed cannulas (e.g., conical versus cylindrical-shaped cannulas), coupled to the increased diffusion time from the reservoir to the core-shell cannula, reduced the core-shell cannulas’ ability to rapidly adjust to environmental glucose-concentrations.
[0174] For example, when the core- shell cannula assumes a cylindrical shape rather than the conical one that facilitates insertion, a more rapid glucose-responsive profile may be observed (Figures 18A, 18B, 18C). While in a clinical setting, such large fluctuations in glucose are mediated by bolus injections of glucose or insulin in the case of hypo or hyper-glycemia, respectively, rather than by basal insulin, it is nevertheless important that the core-shell cannula
be able to adjust basal-infusion rates as dictated by fluctuating environmental glucose concentrations. Without being bound by any theory, while the indication of a glucose-dependent release profile may corroborate that glucose-sensitive insulin delivery through a core-shell cannula design is feasible, further fine tuning of monomer ratios in the hybrid material, for example by increasing the content of FPBA, may potentially facilitate faster responsiveness.
[0175] After evaluating the basal function of the core-shell cannula, the bolus, or the rapid infusion of a large quantity of insulin, capacity of the device was investigated. To mimic a ‘mealtime’ bolus insulin infusion, 2U of insulin was injected through the bolus-injection port of the device at three different time intervals to mimic a breakfast, lunch, and dinner bolus regime. The bolus injections through the devices were consistent across all three simulated meal challenges, and the quantity of insulin delivered was comparable to that of a direct injection to the collection buffer (Figure 19). Notably, the insulin in the delivery devices maintained their bioactivity for a least one week when stored at room temperature, indicating the potential for longer-term insulin release from the devices (Figure 16D). Collectively, these results may indicate the core-shell cannulas made of the glucose-responsive material supported glucose-mediated insulin release in vitro under physiologically relevant parameters.
EXAMPLE 9
A transcutaneous, externally refillable cannula
[0176] In the instant example, an externally refillable, transcutaneous cannula is examined.
[0177] While the glucose-responsive performance of the cannula in diabetic mice was encouraging, the translational potential of this ends-sealed cannula was quite limited; as currently designed, the fully sealed cannula was not refillable. As such, the cannula would have had to be inserted subcutaneously every three days to offer longer-term glycemic control, which given the volume of the device, is a cumbersome and invasive ordeal. Not to mention that the ends-sealed cannula holds three-day’s worth of insulin at a given time, posing severe safety concerns in the case of device failure; the risk of overdosing on insulin due to cannula damage leading to leaking, for example, becomes a significant concern given that severe hypoglycemia may cause brain damage or even death. To facilitate the translational potential of this technology, a cannula that
was more representative of how typical single-port cannulas infuse insulin in commercially available infusion sets was designed.
[0178] To do so, the glucose-responsive cannula was attached to the mouse VABTM button (INSTECH) (Figures 23A, 23B). The mouse VABTM is a transcutaneous button that — when attached to our glucose-responsive cannula — permits quick, painless, aseptic filling and refilling of insulin in the inserted cannula via a syringe (Figure 23A). By simply modifying the dip-coating fabrication method, we can slip-on a medical grade silicone tube to the non-sealed end of the cannula (Figure 24B), which is then used to tether the cannula to the 22ga connector under the disk of the VABTM transcutaneous button, creating a closed system (Figure 23A). Although not required in clinical settings, the polyester felt attached to the transcutaneous button additionally aids to hold the device in place under the skin which may facilitate improved patency. The glucoseresponsive cannula, when attached to the button, provides the composite device with glucose- dcpcndcnt insulin delivery (Figure 23 A). Collectively, the design of this new prototype is more akin to current insulin infusion sets, whereby a transcutaneous system infuses insulin through a subcutaneous cannula on a continual basis.
[0179] To evaluate this new version of the cannula, the transcutaneous button-connected cannulas were inserted under the skin of STZ-induced diabetic mice (Figure 23B, 24C, 24D). Approximately 10U (~50pL (7.5 mg/mL)) of fresh insulin were used to refill the cannula twice daily. The insulin solution remaining in the device was removed prior to administration of the fresh insulin dose. The BGLs of the mice started decreasing 30 minutes after the cannula insertion, with the stable establishment of normoglycemia (e.g., BGLs within the 100-200 mg/dL range) occurring after approximately one hour (Figure 23C). While there were noticeable drops in BGLs immediately after refilling of the devices with fresh insulin, the refilling action did not induce hypoglycemia during any of the five refilling actions (Figure 23D). Several mice did also experience temporary hyperglycemic peaks, but eventually returned to normoglycemic levels after the refilling action. This refillable insulin infusion set promoted normoglycemia in the mice for three days until hyperglycemia was re-established following the removal of insulin from the device at 72h. Conversely, direct subcutaneous injections of insulin only supported transient glucose control, with BGLs of the mice returning to mildly hyperglycemic levels 4h post injection before returning to fully diabetic states at 12h (Figure 23E).
EXAMPLE 10
Alternative Version of the Invention
[0180] In the instant example, a potential alternate version of the material such as intravaginal insulin delivery rings is examined.
[0181] Non-invasive insulin delivery devices are garnering significant attention to improve the standard of care of self-directed insulin delivery therapies. To this end, the intravaginal space is a promising site for both local and systemic drug delivery and represents an interesting, non- invasive, administration route for compounds with poor oral bioavailability (e.g. proteins). Although sparsely explored, research promisingly demonstrates that a reduction of blood glucose levels in T1D animal models may be possible through intravaginal delivery, with glycemic correction further improved using permeation enhancers. Slightly modifying the dip-coating method used to construct insulin delivery devices is conducible to forming ring-shaped hybrid devices reinforced with silicone molds to create an intravaginal insulin delivery ring (Figure 25).
Claims
1. A device comprising i) one or more hydrogel components and ii) an elastomer.
2. The device of claim 1, any other suitable claim, or any combination of suitable claims, wherein the one or more hydrogel components comprise a glucose binding composition.
3. The device of claim 2, any other suitable claim, or any combination of suitable claims, wherein the glucose binding composition comprises phenylboronic acid (PBA), or wherein the glucose binding composition comprises 4-carboxy-3-fluorophenylboronic acid (FPBA), or wherein the glucose binding composition comprises PBA and FPBA..
4. The device of claim 2, any other suitable claim, or any combination of suitable claims, wherein the glucose binding composition consists essentially of PBA, or wherein the glucose binding composition consists essentially of FPBA, or wherein the glucose binding composition consists essentially of PBA and FPBA.
5. The device of claim 2, any other suitable claim, or any combination of suitable claims, wherein the glucose binding composition consists of PBA, or wherein the glucose binding composition consists of FPBA, or wherein the glucose binding composition consists of PBA and FPBA.
6. The device of claim 1, any other suitable claim, or any combination of suitable claims, wherein the one or more hydrogel components comprise a crosslinker.
7. The device of claim 6, any other suitable claim, or any combination of suitable claims, wherein the crosslinker comprises N, N’-methylenebis(acrylamide) (MBAA).
8. The device of claim 6, any other suitable claim, or any combination of suitable claims, wherein the crosslinker consists essentially of MBAA.
9. The device of claim 6, any other suitable claim, or any combination of suitable claims, wherein the crosslinker consists of MBAA.
10. The device of claim 1, any other suitable claim, or any combination of suitable claims, wherein the one or more hydrogel components comprise a photo initiator.
11. The device of claim 10, any other suitable claim, or any combination of suitable claims, wherein the photo initiator comprises Irgacure 2959 (IR2959).
12. The device of claim 10, any other suitable claim, or any combination of suitable claims, wherein the photo initiator consists essentially of TR2959.
13. The device of claim 10, any other suitable claim, or any combination of suitable claims, wherein the photo initiator consists of IR2959.
14. The device of claim 1, any other suitable claim, or any combination of suitable claims, wherein the elastomer is a polyurethane.
15. The device of claim 14, any other suitable claim, or any combination of suitable claims, wherein the polyurethane comprises a HydroMed D3 polyurethane.
16. The device of claim 14, any other suitable claim, or any combination of suitable claims, wherein the polyurethane consists essentially of a HydroMed D3 polyurethane.
17. The device of claim 14, any other suitable claim, or any combination of suitable claims, wherein the polyurethane consists of a HydroMed D3 polyurethane.
18. The device of claim 14, any other suitable claim, or any combination of suitable claims, wherein the polyurethane is selected from the group consisting of a HydroMed D7, D4, D3, DI, D6, D640 polyurethane, and combinations thereof.
19. The device of claim 1, any other suitable claim, or any combination of suitable claims, wherein the elastomer is a product of an elastomer solution.
20. The device of claim 19, any other suitable claim, or any combination of suitable claims, wherein the elastomer solution comprises a concentration of 18 wt%.
21. The device of claim 19, any other suitable claim, or any combination of suitable claims, wherein the elastomer solution comprises a concentration of 16-20 wt%.
22. The device of claim 1, any other suitable claim, or any combination of suitable claims, wherein the elastomer forms an elastomeric network.
23. The device of claim 1, any other suitable claim, or any combination of suitable claims, wherein the hydrogel components form a hydrogel.
24. The device of claim 23, any other suitable claim, or any combination of suitable claims, wherein the hydrogel is photocrosslinked.
25. The device of claim 23, any other suitable claim, or any combination of suitable claims, wherein the hydrogel is contained in an elastomeric network.
26. The device of claim 25, any other suitable claim, or any combination of suitable claims, wherein the hydrogel-elastomeric network forms an interpenetrating network.
27. The device of claim 26, any other suitable claim, or any combination of suitable claims, wherein the interpenetrating network is configured to release insulin.
28. The device of claim 27, any other suitable claim, or any combination of suitable claims, wherein the insulin can be released from any portion of the interpenetrating network.
29. The device of claim 27, any other suitable claim, or any combination of suitable claims, wherein the insulin can be released from one or more non-perf orated portions of the interpenetrating network.
30. The device of claim 1, any other suitable claim, or any combination of suitable claims, wherein the device further comprises insulin.
31. The device of claim 30, any other suitable claim, or any combination of suitable claims, wherein the insulin is a fast acting insulin.
32. The device of claim 30, any other suitable claim, or any combination of suitable claims, wherein the insulin is a long acting insulin.
33. The device of claim 30, any other suitable claim, or any combination of suitable claims, wherein the insulin comprises a fast acting insulin, a long acting insulin, or a combination thereof.
34. The device of claim 1, any other suitable claim, or any combination of suitable claims, wherein the device is irradiated.
35. The device of claim 34, any other suitable claim, or any combination of suitable claims, wherein the irradiation is ultraviolet irradiation.
36. The device of claim 1, any other suitable claim, or any combination of suitable claims, wherein the device is configured to comprise a therapeutic agent.
37. The device of claim 36, any other suitable claim, or any combination of suitable claims, wherein the therapeutic agent is insulin.
38. The device of claim 36, any other suitable claim, or any combination of suitable claims, wherein the insulin is a fast acting insulin.
39. The device of claim 36, any other suitable claim, or any combination of suitable claims, wherein the insulin is a long acting insulin.
40. The device of claim 39, any other suitable claim, or any combination of suitable claims, wherein the insulin comprises a fast acting insulin, a long acting insulin, or a combination thereof.
41. The device of claim 1, any other suitable claim, or any combination of suitable claims, wherein the device is configured to contain a surfactant.
42. The device of claim 41, any other suitable claim, or any combination of suitable claims, wherein the surfactant is a non-ionic surfactant.
43. The device of claim 41, any other suitable claim, or any combination of suitable claims, wherein the surfactant comprises n-Octyl-|3-d-glucoside.
44. The device of claim 41, any other suitable claim, or any combination of suitable claims, wherein the surfactant consists essentially of zz-Octyl-P-d-glucoside.
45. The device of claim 41, any other suitable claim, or any combination of suitable claims, wherein the surfactant consists of zz-Octyl-P-d-glucoside.
46. The device of claim 1, any other suitable claim, or any combination of suitable claims, wherein the device is configured to absorb glucose.
47. The device of claim 46, any other suitable claim, or any combination of suitable claims, wherein the device is a permeable device for the absorption of glucose.
48. The device of claim 46, any other suitable claim, or any combination of suitable claims, wherein the absorption occurs in a glucose responsive manner.
49. The device of claim 46, any other suitable claim, or any combination of suitable claims, wherein the absorption occurs under hypoglycemic conditions.
50. The device of claim 46, any other suitable claim, or any combination of suitable claims, wherein the absorption occurs under hyperglycemic conditions.
51. The device of claim 1, any other suitable claim, or any combination of suitable claims, wherein the device is implantable.
52. The device of claim 51, any other suitable claim, or any combination of suitable claims, wherein the implantable device is removable.
53. The device of claim 1, any other suitable claim, or any combination of suitable claims, wherein the device does not comprise a glucose-responsive plug.
54. The device of claim 1, any other suitable claim, or any combination of suitable claims, wherein the device is substantially free of electronics.
55. The device of claim 1, any other suitable claim, or any combination of suitable claims, wherein the device is a tube.
56. The device of claim 55, any other suitable claim, or any combination of suitable claims, wherein the tube is sealed with a thermoseal.
57. The device of claim 55, any other suitable claim, or any combination of suitable claims, wherein the tube is sealed at a first end of the tube, at a second end of the tube, or both.
58. The device of claim 57, any other suitable claim, or any combination of suitable claims, wherein the first end of the tube is sealed with a thermoseal.
59. The device of claim 57, any other suitable claim, or any combination of suitable claims, wherein the second end of the tube is sealed with a thermoseal.
60. The device of claim 57, any other suitable claim, or any combination of suitable claims, wherein the first end of the tube is sealed with a thermoseal and the second end of the tube is sealed with a thermoseal.
61. The device of claim 1, any other suitable claim, or any combination of suitable claims, wherein the device is a cannula.
62. The device of claim 1 , any other suitable claim, or any combination of suitable claims, wherein the device is a ring-shaped device.
63. The device of claim 1, any other suitable claim, or any combination of suitable claims, wherein the device is an intravaginal delivery device.
64. A process for producing a device, the process comprising the steps of: d) combining one or more hydrogel components and a liquid composition comprising an elastomer to form a liquid combination, e) evaporating the liquid combination to form a hydrogel matrix, f) irradiating the hydrogel matrix to form the device.
65. The process of claim 64, any other suitable claim, or any combination of suitable claims, wherein the process is performed via a one-pot system.
66. The process of claim 64, any other suitable claim, or any combination of suitable claims, wherein the device is an interpenetrating network.
67. The process of claim 64, any other suitable claim, or any combination of suitable claims, wherein the liquid composition comprising an elastomer is a solution.
68. The process of claim 67, any other suitable claim, or any combination of suitable claims, wherein the elastomer solution comprises a concentration of 18 wt%.
69. The process of claim 67, any other suitable claim, or any combination of suitable claims, wherein the elastomer solution comprises a concentration of 16-20 wt%.
70. The process of claim 64, any other suitable claim, or any combination of suitable claims, wherein the process comprises use of a mold to form the device.
71. The process of claim 70, any other suitable claim, or any combination of suitable claims, wherein the liquid combination of step a) is placed in the mold.
72. The process of claim 70, any other suitable claim, or any combination of suitable claims, wherein step b) is performed on the liquid combination in the mold.
73. The process of claim 70, any other suitable claim, or any combination of suitable claims, wherein step c) is performed on the hydrogel matrix in the mold.
74. The process of claim 70, any other suitable claim, or any combination of suitable claims, wherein the process further comprises a step d), wherein step d) comprises removing the device from the mold.
75. The process of claim 74, any other suitable claim, or any combination of suitable claims, wherein step d) comprises placing the device in water.
76. The process of claim 64, any other suitable claim, or any combination of suitable claims, wherein the irradiation is ultraviolet irradiation.
77. The process of claim 64, any other suitable claim, or any combination of suitable claims, wherein the hydrogel matrix is photocrosslinked.
78. The process of claim 64, any other suitable claim, or any combination of suitable claims, wherein the process further comprises a step of adding insulin to the device.
79. The process of claim 78, any other suitable claim, or any combination of suitable claims, wherein the insulin is a fast acting insulin.
80. The process of claim 78, any other suitable claim, or any combination of suitable claims, wherein the insulin is a long acting insulin.
81. The process of claim 78, any other suitable claim, or any combination of suitable claims, wherein the insulin comprises a fast acting insulin, a long acting insulin, or a combination thereof.
82. The process of claim 64, any other suitable claim, or any combination of suitable claims, wherein the process further comprises a step of adding a surfactant to the device.
83. The process of claim 82, any other suitable claim, or any combination of suitable claims, wherein the surfactant is a non-ionic surfactant.
84. The process of claim 82, any other suitable claim, or any combination of suitable claims, wherein the surfactant comprises n-Octyl-β-d-glucoside.
85. The process of claim 82, any other suitable claim, or any combination of suitable claims, wherein the surfactant consists essentially of n-Octyl-β-d-glucoside.
86. The process of claim 82, any other suitable claim, or any combination of suitable claims, wherein the surfactant consists of n-Octyl-β-d-glucoside.
87. The process of claim 64, any other suitable claim, or any combination of suitable claims, wherein the one or more hydrogel components comprise a glucose binding composition.
88. The process of claim 87, any other suitable claim, or any combination of suitable claims, wherein the glucose binding composition comprises phenylboronic acid (PBA), or wherein the glucose binding composition comprises 4-carboxy-3-fluorophenylboronic acid (FPBA), or wherein the glucose binding composition comprises PBA and FPB A.
89. The process of claim 87, any other suitable claim, or any combination of suitable claims, wherein the glucose binding composition consists essentially of PBA, or wherein the glucose binding composition consists essentially of FPBA, or wherein the glucose binding composition consists essentially of PBA and FPBA.
90. The process of claim 87, any other suitable claim, or any combination of suitable claims, wherein the glucose binding composition consists of PBA, or wherein the glucose binding composition consists of FPBA, or wherein the glucose binding composition consists of PBA and FPBA.
91. The process of claim 64, any other suitable claim, or any combination of suitable claims, wherein the one or more hydrogel components comprise a crosslinker.
92. The process of claim 91, any other suitable claim, or any combination of suitable claims, wherein the crosslinker comprises N, N’-methylenebis(acrylamide) (MBAA).
93. The process of claim 91, any other suitable claim, or any combination of suitable claims, wherein the crosslinker consists essentially of MBAA.
94. The process of claim 91, any other suitable claim, or any combination of suitable claims, wherein the crosslinker consists of MBAA.
95. The process of claim 64, any other suitable claim, or any combination of suitable claims, wherein the one or more hydrogel components comprise a photo initiator.
96. The process of claim 95, any other suitable claim, or any combination of suitable claims, wherein the photo initiator comprises Irgacure 2959 (IR2959).
97. The process of claim 95, any other suitable claim, or any combination of suitable claims, wherein the photo initiator consists essentially of IR2959.
98. The process of claim 95, any other suitable claim, or any combination of suitable claims, wherein the photo initiator consists of IR2959.
99. The process of claim 64, any other suitable claim, or any combination of suitable claims, wherein the elastomer is a polyurethane.
100. The process of claim 99, any other suitable claim, or any combination of suitable claims, wherein the polyurethane comprises a HydroMed D3 polyurethane.
101. The process of claim 99, any other suitable claim, or any combination of suitable claims, wherein the polyurethane consists essentially of a HydroMed D3 polyurethane.
102. The process of claim 99, any other suitable claim, or any combination of suitable claims, wherein the polyurethane consists of a HydroMed D3 polyurethane.
103. The process of claim 99, any other suitable claim, or any combination of suitable claims, wherein the polyurethane is selected from the group consisting of a HydroMed D7, D4, D3, DI, D6, D640 polyurethane, and combinations thereof.
104. The process of claim 64, any other suitable claim, or any combination of suitable claims, wherein the elastomer forms an elastomeric network.
105. The process of claim 64, any other suitable claim, or any combination of suitable claims, wherein the device is configured to absorb glucose.
106. The process of claim 105, any other suitable claim, or any combination of suitable claims, wherein the device is a permeable device for the absorption of glucose.
107. The process of claim 105, any other suitable claim, or any combination of suitable claims, wherein the absorption occurs in a glucose responsive manner.
108. The process of claim 105, any other suitable claim, or any combination of suitable claims, wherein the absorption occurs under hypoglycemic conditions.
109. The process of claim 105, any other suitable claim, or any combination of suitable claims, wherein the absorption occurs under hyperglycemic conditions.
110. The process of claim 64, any other suitable claim, or any combination of suitable claims, wherein the device is implantable.
111. The process of claim 110, any other suitable claim, or any combination of suitable claims, wherein the implantable device is removable.
112. The process of claim 64, any other suitable claim, or any combination of suitable claims, wherein the device does not comprise a glucose-responsive plug.
113. The process of claim 64, any other suitable claim, or any combination of suitable claims, wherein the device is substantially free of electronics.
114. The process of claim 64, any other suitable claim, or any combination of suitable claims, wherein the device is a tube.
115. The process of claim 114, any other suitable claim, or any combination of suitable claims, wherein the tube is sealed with a thermoseal.
116. The process of claim 114, any other suitable claim, or any combination of suitable claims, wherein the tube is sealed at a first end of the tube, at a second end of the tube, or both.
117. The process of claim 116, any other suitable claim, or any combination of suitable claims, wherein the first end of the tube is sealed with a thermoseal.
118. The process of claim 116, any other suitable claim, or any combination of suitable claims, wherein the second end of the tube is sealed with a thermoseal.
119. The process of claim 116, any other suitable claim, or any combination of suitable claims, wherein the first end of the tube is sealed with a thermoseal and the second end of the tube is sealed with a thermo seal.
120. The process of claim 64, any other suitable claim, or any combination of suitable claims, wherein the device is a cannula.
121. The process of claim 64, any other suitable claim, or any combination of suitable claims, wherein the device is a ring-shaped device.
122. The process of claim 64, any other suitable claim, or any combination of suitable claims, wherein the device is an intravaginal delivery device.
123. A method of treating a disease in a subject using the device of any one of claims 1 to 63, the method comprising the step of administering insulin to the subject via the device.
124. The method of claim 123, any other suitable claim, or any combination of suitable claims, wherein the device is implanted in the subject.
125. The method of claim 124, any other suitable claim, or any combination of suitable claims, wherein the device is subsequently removed from the subject.
126. The method of claim 123, any other suitable claim, or any combination of suitable claims, wherein the disease is a glucose-responsive disease.
127. The method of claim 123, any other suitable claim, or any combination of suitable claims, wherein the disease is diabetes.
128. The method of claim 127, any other suitable claim, or any combination of suitable claims, wherein the diabetes is Type 1 diabetes.
129. The method of claim 127, any other suitable claim, or any combination of suitable claims, wherein the diabetes is Type 2 diabetes.
130. The method of claim 123, any other suitable claim, or any combination of suitable claims, wherein the device is a tube.
131. The method of claim 123, any other suitable claim, or any combination of suitable claims, wherein the device is a cannula.
132. The method of claim 123, any other suitable claim, or any combination of suitable claims, wherein the device is a ring-shaped device.
133. The method of claim 123, any other suitable claim, or any combination of suitable claims, wherein the device is an intravaginal delivery device.
134. A kit comprising ii) one or more hydrogel components, ii) an elastomer, and iii) instructions for producing a device.
135. The kit of claim 134, any other suitable claim, or any combination of suitable claims, wherein the one or more hydrogel components comprise a glucose binding composition.
136. The kit of claim 135, any other suitable claim, or any combination of suitable claims, wherein the glucose binding composition comprises phenylboronic acid (PBA), or wherein the glucose binding composition comprises 4-carboxy-3-fluorophenylboronic acid (FPBA), or wherein the glucose binding composition comprises PBA and FPBA.
137. The kit of claim 135, any other suitable claim, or any combination of suitable claims, wherein the glucose binding composition consists essentially of PBA, or wherein the glucose binding composition consists essentially of FPBA, or wherein the glucose binding composition consists essentially of PBA and FPBA.
138. The kit of claim 135, any other suitable claim, or any combination of suitable claims, wherein the glucose binding composition consists of PB A, or wherein the glucose binding composition consists of FPBA, or wherein the glucose binding composition consists of PB A and FPBA.
139. The kit of claim 134, any other suitable claim, or any combination of suitable claims, wherein the one or more hydrogel components comprise a crosslinker.
140. The kit of claim 139, any other suitable claim, or any combination of suitable claims, wherein the crosslinker comprises N, N’-methylenebis(acrylamide) (MBAA).
141. The kit of claim 139, any other suitable claim, or any combination of suitable claims, wherein the crosslinker consists essentially of MBAA.
142. The kit of claim 139, any other suitable claim, or any combination of suitable claims, wherein the crosslinker consists of MBAA.
143. The kit of claim 134, any other suitable claim, or any combination of suitable claims, wherein the one or more hydrogel components comprise a photo initiator.
144. The kit of claim 143, any other suitable claim, or any combination of suitable claims, wherein the photo initiator comprises Irgacure 2959 (IR2959).
145. The kit of claim 143, any other suitable claim, or any combination of suitable claims, wherein the photo initiator consists essentially of IR2959.
146. The kit of claim 143, any other suitable claim, or any combination of suitable claims, wherein the photo initiator consists of IR2959.
147. The kit of claim 134, any other suitable claim, or any combination of suitable claims, wherein the elastomer is a polyurethane.
148. The kit of claim 147, any other suitable claim, or any combination of suitable claims, wherein the polyurethane comprises a HydroMed D3 polyurethane.
149. The kit of claim 147, any other suitable claim, or any combination of suitable claims, wherein the polyurethane consists essentially of a HydroMed D3 polyurethane.
150. The kit of claim 147, any other suitable claim, or any combination of suitable claims, wherein the polyurethane consists of a HydroMed D3 polyurethane.
151. The kit of claim 147, any other suitable claim, or any combination of suitable claims, wherein the polyurethane is selected from the group consisting of a HydroMed D7, D4, D3, DI , D6, D640 polyurethane, and combinations thereof.
152. The kit of claim 134, any other suitable claim, or any combination of suitable claims, wherein the elastomer is a product of an elastomer solution.
153. The kit of claim 152, any other suitable claim, or any combination of suitable claims, wherein the elastomer solution comprises a concentration of 18 wt%.
154. The kit of claim 152, any other suitable claim, or any combination of suitable claims, wherein the elastomer solution comprises a concentration of 16-20 wt%.
155. The kit of claim 134, any other suitable claim, or any combination of suitable claims, wherein the elastomer forms an elastomeric network.
156. The kit of claim 134, any other suitable claim, or any combination of suitable claims, wherein the hydrogel components form a hydrogel.
157. The kit of claim 156, any other suitable claim, or any combination of suitable claims, wherein the hydrogel is photocrosslinked.
158. The kit of claim 156, any other suitable claim, or any combination of suitable claims, wherein the hydrogel is contained in an elastomeric network.
159. The kit of claim 158, any other suitable claim, or any combination of suitable claims, wherein the hydrogel-elastomeric network forms an interpenetrating network.
160. The kit of claim 159, any other suitable claim, or any combination of suitable claims, wherein the interpenetrating network is configured to release insulin.
161. The kit of claim 160, any other suitable claim, or any combination of suitable claims, wherein the insulin can be released from any portion of the interpenetrating network.
162. The kit of claim 160, any other suitable claim, or any combination of suitable claims, wherein the insulin can be released from one or more non-perforated portions of the interpenetrating network.
163. The kit of claim 134, any other suitable claim, or any combination of suitable claims, wherein the device further comprises insulin.
164. The kit of claim 163, any other suitable claim, or any combination of suitable claims, wherein the insulin is a fast acting insulin.
165. The kit of claim 163, any other suitable claim, or any combination of suitable claims, wherein the insulin is a long acting insulin.
166. The kit of claim 163, any other suitable claim, or any combination of suitable claims, wherein the insulin comprises a fast acting insulin, a long acting insulin, or a combination thereof.
167. The kit of claim 134, any other suitable claim, or any combination of suitable claims, wherein the device is irradiated.
168. The kit of claim 167, any other suitable claim, or any combination of suitable claims, wherein the irradiation is ultraviolet irradiation.
169. The kit of claim 134, any other suitable claim, or any combination of suitable claims, wherein the device is configured to comprise a therapeutic agent.
170. The kit of claim 169, any other suitable claim, or any combination of suitable claims, wherein the therapeutic agent is insulin.
171. The kit of claim 169, any other suitable claim, or any combination of suitable claims, wherein the insulin is a fast acting insulin.
172. The kit of claim 169, any other suitable claim, or any combination of suitable claims, wherein the insulin is a long acting insulin.
173. The kit of claim 172, any other suitable claim, or any combination of suitable claims, wherein the insulin comprises a fast acting insulin, a long acting insulin, or a combination thereof.
174. The kit of claim 134, any other suitable claim, or any combination of suitable claims, wherein the device is configured to contain a surfactant.
175. The kit of claim 174, any other suitable claim, or any combination of suitable claims, wherein the surfactant is a non-ionic surfactant.
176. The kit of claim 174, any other suitable claim, or any combination of suitable claims, wherein the surfactant comprisens-Octyl-β-d-glucoside .
177. The kit of claim 174, any other suitable claim, or any combination of suitable claims, wherein the surfactant consists essentially of n-Octyl-β-d-glucoside .
178. The kit of claim 174, any other suitable claim, or any combination of suitable claims, wherein the surfactant consists ofn-Octyl-β-d-glucoside .
179. The kit of claim 134, any other suitable claim, or any combination of suitable claims, wherein the device is configured to absorb glucose.
180. The kit of claim 179, any other suitable claim, or any combination of suitable claims, wherein the device is a permeable device for the absorption of glucose.
181. The kit of claim 179, any other suitable claim, or any combination of suitable claims, wherein the absorption occurs in a glucose responsive manner.
182. The kit of claim 179, any other suitable claim, or any combination of suitable claims, wherein the absorption occurs under hypoglycemic conditions.
183. The kit of claim 179, any other suitable claim, or any combination of suitable claims, wherein the absorption occurs under hyperglycemic conditions.
184. The kit of claim 134, any other suitable claim, or any combination of suitable claims, wherein the device is implantable.
185. The kit of claim 184, any other suitable claim, or any combination of suitable claims, wherein the implantable device is removable.
186. The kit of claim 134, any other suitable claim, or any combination of suitable claims, wherein the device does not comprise a glucose-responsive plug.
187. The kit of claim 134, any other suitable claim, or any combination of suitable claims, wherein the device is substantially free of electronics.
188. The kit of claim 134, any other suitable claim, or any combination of suitable claims, wherein the device is a tube.
189. The kit of claim 188, any other suitable claim, or any combination of suitable claims, wherein the tube is sealed with a thermoseal.
190. The kit of claim 188, any other suitable claim, or any combination of suitable claims, wherein the tube is sealed at a first end of the tube, at a second end of the tube, or both.
191. The kit of claim 190, any other suitable claim, or any combination of suitable claims, wherein the first end of the tube is sealed with a thermoseal.
192. The kit of claim 190, any other suitable claim, or any combination of suitable claims, wherein the second end of the tube is sealed with a thermoseal.
193. The kit of claim 190, any other suitable claim, or any combination of suitable claims, wherein the first end of the tube is sealed with a thermoseal and the second end of the tube is sealed with a thermo seal.
194. The kit of claim 134, any other suitable claim, or any combination of suitable claims, wherein the device is a cannula.
195. The kit of claim 134, any other suitable claim, or any combination of suitable claims, wherein the device is a ring-shaped device.
196. The kit of claim 134, any other suitable claim, or any combination of suitable claims, wherein the device is an intravaginal delivery device.
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Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
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US20130261212A1 (en) * | 2008-08-05 | 2013-10-03 | David Myung | Polyurethane-grafted hydrogels |
US20180296722A1 (en) * | 2013-07-01 | 2018-10-18 | Trustees Of Boston University | Dissolvable hydrogel compositions for wound management and methods of use |
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Publication number | Priority date | Publication date | Assignee | Title |
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US20130261212A1 (en) * | 2008-08-05 | 2013-10-03 | David Myung | Polyurethane-grafted hydrogels |
US20180296722A1 (en) * | 2013-07-01 | 2018-10-18 | Trustees Of Boston University | Dissolvable hydrogel compositions for wound management and methods of use |
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