Implantable Sensors

Abstract

The present invention provides an implantable synthetic patch comprising at least one porous polymer and at least one sensor, switch sensor and / or transmitter, and its use in diagnosing a disease, condition, disorder or state in a subject in need thereof.

Description

[Background technology]

[0001] Precision medicine can be defined as the prevention, investigation and treatment of disease taking into account individual differences. There are multiple ways in which the field of precision medicine can advance; however, recent innovations in the fields of electronics and microfabrication technologies have led to an increased interest in the use of implantable biosensors in precision medicine.

[0002] Implantable biosensors are an important class of biosensors due to their ability to provide continuous data about the levels of target analytes; this allows for monitoring trends and changes in analyte levels over time without the need for intervention by either the patient or the clinician. As such, implantable biosensors have great potential in the diagnosis, monitoring, management and treatment of various disease conditions.

[0003] In most cases, especially when long-term monitoring of a subject's condition is required by biosensors that can be implanted in the body, the host immune response will induce unwanted, adverse effects and rejection of the implant, endangering the subject's health and necessitating removal of the implant and re-implantation of another one.

[0004] There is a continuing need to provide safe, biocompatible implantable devices capable of continuously monitoring a subject with minimal intervention compared to common procedures in a clinical setting. Summary of the Invention

[0005] The present invention provides an implantable synthetic patch comprising at least one porous polymer and at least one sensor and / or transmitter.

[0006] When referring to a sensor (or transducer), it should be understood to encompass a device that translates at least one physical characteristic (pressure, temperature, humidity, heart rate, levels of biological compounds found in bodily fluids, such as, for example, glucose, hormones, insulin, etc.) into an electrical signal. When referring to a transmitter, it should be understood to refer to a sensor that carries data over long distances (e.g., the data can be read by a remote controlling / reading / receiving / receiver device, such as a handheld computer, computer, phone, etc.). Another type of sensor that can be used in the implantable synthetic patch of the invention is a switch sensor, which is defined as a sensor that holds a threshold (X) and outputs a true or false indication. For example, if the measured pressure > (X), output true, otherwise output false.

[0007] In some embodiments, the at least one sensor and / or transmitter is a wireless sensor and / or transmitter.

[0008] In some embodiments, the implantable synthetic patch of the invention further comprises at least one microprocessor. In some embodiments, the implantable synthetic patch of the invention further comprises at least one WiFi and / or Bluetooth transmitter. In some embodiments, the implantable synthetic patch of the invention further comprises at least one receiver.

[0009] Thus, the present invention provides an implantable synthetic patch comprising at least one porous polymer and at least one sensor. Additionally, the present invention provides an implantable synthetic patch comprising at least one porous polymer and at least one transmitter.

[0010] The devices of the present invention are implantable and can be placed within the human body for a predetermined period of time. In some embodiments, the devices of the invention can be implanted under the skin (transdermal) and / or skin tissue (integumentary, endothelial tissue, etc.) of a subject. In other embodiments, the devices of the invention can be implanted on an organ or part thereof (e.g. - pancreas, heart, uterus, gland, brain, colon, liver, stomach, lungs, muscle, and any combination thereof), internally, or externally of a subject.

[0011] In some embodiments, the implantable synthetic patch of the invention is a biocompatible patch.

[0012] In some embodiments, the implantable synthetic patch of the invention is a biodegradable patch.

[0013] In some embodiments, the implantable synthetic patch of the invention is a non-biodegradable patch.

[0014] In some embodiments, the at least one porous polymer has pores with pores less than 5 microns.

[0015] In some embodiments, the at least one porous polymer has pores between 1 and 5 microns.

[0016] In some embodiments, the at least one porous polymer has pores between 5 and 20 microns.

[0017] In some embodiments, the implantable synthetic patch of the invention has a thickness of 50-250 microns, hi other embodiments, the patch has a thickness of 250-2500 microns.

[0018] In some embodiments, the at least one sensor and / or transmitter is fully embedded / encapsulated within the polymer patch comprising at least one porous polymer. In some embodiments, the at least one sensor and / or transmitter is at least partially embedded / encapsulated within the polymer patch comprising at least one porous polymer. In other embodiments, the implantable synthetic patch of the invention further comprises at least one semi-permeable layer that selectively allows at least one biological compound (e.g.: certain peptides, hormones, i.e. insulin, thyroxine, nutrients such as glucose, pH, drugs, chemotherapeutic agents) to pass through the pores of the patch.

[0019] The term "porous biocompatible layer" should be understood to encompass any type of layer (or film) formed from a material capable of performing its desired function. The layer should not induce undesirable local or systemic effects in the recipient or beneficiary of the therapy, while generating the most appropriate and beneficial cellular or tissue response in the particular situation, optimizing the clinically relevant outcome of the therapy. The biocompatible layer of the inventive device allows the implanted patch to exist in harmony with the tissue it contacts without causing adverse changes. The layer is porous, and in some embodiments, said layer has a pore size of at least about 2 μm (when referring to pore size, it should be understood to refer to the average pore size).

[0020] In some embodiments, the porous polymer structure comprises nanofibers. In other embodiments, the porous polymer structure comprises at least one porous electrospun polymer. In further embodiments, the porous polymer structure comprises an aromatic polyurethane, polycarbonate, poly(DTE carbonate), polycaprolactone (PCL), polylactic acid (PLA), poly-L-lactic acid (PLLA), poly(DL-lactide-co-caprolactone, poly(ethylene-co-vinyl acetate), vinyl acetate, poly(methyl methacrylate), poly(propylene carbonate), poly(vinylidene fluoride), polyacrylonitrile, polycaprolactone, polycarbomethylsilane, polylactic acid, polystyrene, polyvinylpyrrolidone, polyvinyl alcohol. The polymer may comprise at least one polymer selected from polyvinyl alcohol (PVA), polyethylene oxide (PEO), polyurethane, polyvinyl chloride (PVC), hyaluronic acid (HA), chitosan, alginate, polyhydroxybutyrate and its copolymers, nylon 11, cellulose acetate, hydroxyappetite, poly(3-hydroxybutyrate-co-3-hydroxyvalerate), poly(DL-lactide), polycaprolactone, and poly(L-lactide), or any combination thereof.

[0021] In some embodiments, the implantable synthetic patch of the invention further comprises at least one active agent, hi some embodiments, the at least one active agent is contained within the implantable patch of the invention in the form of a metered and / or gated release reservoir.

[0022] The term "electrospinning" or "electrospinning" or any of its lingual deviations should be understood to encompass the process of using an electric charge to draw very fine (typically micro- or nanoscale) fibers from a liquid. Electrospinning from a molten precursor can also be performed; this method ensures that no solvent can be carried over into the final product. Fibers produced using the electrospinning process have an increased surface area to volume ratio. Various factors are known to affect electrospun fibers, including but not limited to: solution viscosity, surface tension, electric field strength, and distance.

[0023] In a typical electrospinning process, a sufficiently high voltage is applied to a droplet of polymeric material (polymer solution, its monomer precursor, sol-gel precursor, particulate suspension or melt), the liquid body becomes charged, electrostatic repulsion opposes surface tension, the droplets are elongated, and at a critical point, a liquid stream ejects from the surface. If the molecular cohesion of the liquid is high enough, no shunting occurs (otherwise the droplets would be electrosprayed) and a charged liquid jet is formed. As the jet dries in flight, the current flow changes from ohmic to convective as charge is transferred to the surface of the fiber. The jet is then stretched by a whipping process driven by electrostatic repulsion that initiates small bends in the fiber until it is finally deposited on a grounded collector. This stretching and thinning of the fiber due to bending instability leads to the formation of uniform fibers with nanometer-scale diameters.

[0024] Biocompatible polymers that can be applied in the electrospinning process include, but are not limited to, poly(DTE carbonate), polycaprolactone (PCL), polylactic acid (PLA), poly-L-lactic acid (PLLA), poly(DL-lactide-co-caprolactone, poly(ethylene-co-vinyl acetate), vinyl acetate, poly(methyl methacrylate), poly(propylene carbonate), poly(vinylidene fluoride), polyacrylonitrile, polycaprolactone, polycarbomethylsilane, polylactic acid, polystyrene, polyvinylpyrrolidone, polyvinyl alcohol (P Polyvinyl chloride (PVC), hyaluronic acid (HA), chitosan, alginate, polyhydroxybuyrate and its copolymers, nylon 11, cellulose acetate, hydroxyappetite, or any combination thereof. Polymers include, but are not limited to: poly(3-hydroxybutyrate-co-3-hydroxyvalerate), poly(DL-lactide), polyurethane, polycaprolactone, and poly(L-lactide), or any combination thereof.

[0025] Electrospun fibers are typically several orders of magnitude smaller than those produced using conventional spinning techniques. By optimizing parameters such as: i) the intrinsic properties of the solution, e.g., polarity and surface tension of the solvent, molecular weight and conformation of the polymer chains, and viscosity, elasticity, and electrical conductivity of the solution; and ii) the operating conditions, e.g., electric field strength, distance between the spinneret and the collector, and solution feed rate, electrospinning can produce fibers as thin as tens of nanometers in diameter. Additional parameters that affect the properties of electrospun fibers include the polymer molecular weight, molecular weight distribution and structure (branched, linear, etc.), solution properties (viscosity, electrical conductivity, and surface tension), electric potential, flow rate and concentration, distance between the capillary and the collection screen, ambient parameters (temperature, humidity, and air velocity in the chamber), target screen (collector) movement, etc. The production of highly porous fibers can be achieved by electrospinning the jet directly into the cryogenic liquid. Well-defined pores appeared on the surface of each fiber as a result of temperature-induced phase separation between the polymer and the solvent and evaporation of the solvent under freeze-drying conditions.

[0026] Several approaches have been developed to organize electrospun fibers into aligned arrays. For example, electrospun fibers can be aligned into uniaxial arrays by replacing the single-piece collector with a pair of conducting substrates separated by an air gap. In this case, the nanofibers tend to be elongated across the gap oriented perpendicular to the ends of the electrodes. It has also been shown that the counterelectrode can be patterned on an insulating substrate such as quartz or polystyrene, so that the uniaxially aligned fibers can be stacked layer by layer into a 3D lattice. By controlling the electrode pattern and / or the sequence for applying the high voltage, it is also possible to generate more complex structures consisting of well-aligned nanofibers.

[0027] Electrospun nanofibers can also be directly deposited onto various objects, resulting in nanofiber-based constructs with well-defined and controllable shapes. In addition, after electrospinning, the aligned or randomly oriented nanofiber membranes can be manually manipulated into various types of constructs: for example, winding the fibrous membrane to create tubes, or punching the fibrous membrane to prepare disks with controllable diameters.

[0028] The present invention relates to any electrospinning method known in the art, including: Electrospinning, J. Stanger, N. Tucker, and M. Staiger, I-Smithers Rapra publishing (UK), An Introduction to Electrospinning and Nanofibers, S. Ramakrishna, K. Fujihara, WE Teo, World Scientific Publishing Co. Pte Ltd (Jun 2005), Electrospinning of micro- and nanofibers: fundamentals and applications in separation and filtration processes, Y. Fillatov, A. Budyka, and V. Kirichenko (Trans. D. Letterman), Begell House Inc., New York, USA, 2007, all of which are incorporated herein by reference in their entireties.

[0029] Suitable electrospinning techniques are disclosed, for example, in International Patent Application Publication Nos. WO2002 / 049535, WO2002 / 049536, WO2002 / 049536, WO2002 / 049678, WO2002 / 074189, WO2002 / 074190, WO2002 / 074191, WO2005 / 032400 and WO2005 / 065578, the contents of which are hereby incorporated by reference. In accordance with a presently preferred embodiment of the invention, particular emphasis has been placed on electrospinning techniques, but it should be understood that it is not intended to limit the scope of the invention to electrospinning techniques. Representative examples of other spinning techniques suitable for this embodiment include, but are not limited to, wet spinning, dry spinning, gel spinning, dispersion spinning, reaction spinning, or tuck spinning techniques. Such and other spinning techniques are known in the art and are disclosed, for example, in U.S. Pat. Nos. 3,737,508, 3,950,478, 3,996,321, 4,189,336, 4,402,900, 4,421,707, 4,431,602, 4,557,732, 4,643,657, 4,804,511, 5,002,474, 5,122,329, 5,387,387, 5,667,743, 6,248,273 and 6,252,031, the contents of which are hereby incorporated by reference.

[0030] In some embodiments, the at least one active agent is selected from a protein, collagen, fibronectin, or TGF-β2, heparin, a growth factor, an antibody, an antimetabolite, a chemotherapeutic agent, an anti-inflammatory agent, an antibiotic agent, an antimicrobial agent, and any combination thereof.

[0031] In some embodiments, the at least one sensor is a biosensor. In some embodiments, the at least one sensor is a biotransmitter (i.e., a sensor and / or transmitter adapted to sense at least one biological property).

[0032] The biosensor is an analytical device used for the detection of chemicals, which combines a biological component with a physicochemical detector. Sensitive biological components, such as tissues, microorganisms, organelles, cell receptors, enzymes, antibodies, nucleic acids, etc., are biologically derived or biomimetic components that interact, bind, or recognize the analyte under study. Biological sensitive components can also be bioengineered. Transducers or sensing elements convert one signal into another and function in a physicochemical manner: optical, piezoelectric, electrochemical, electrochemiluminescence, etc., resulting from the interaction of the analyte with the biological component, which can be easily measured and quantified. In some embodiments, the biosensor reader is connected to an electronics or signal processor that is primarily associated with the display of the results.

[0033] Biosensors typically consist of a bioreceptor (enzyme / antibody / cell / nucleic acid / aptamer), a transducer component (semiconductor material / nanomaterial), and an electronic system including a signal amplifier, processor, and display. The transducer and electronics can be combined, for example, in a CMOS-based microsensor system. The recognition component, often called a bioreceptor, interacts with the analyte of interest using a biomolecule derived from a living organism or a receptor modeled on a biological system. This interaction is measured by a biotransducer that outputs a measurable signal proportional to the presence of the target analyte in the sample. The general goal of biosensor design is to enable rapid and convenient testing at the relevant time of sample acquisition or at the point of care.

[0034] In some embodiments, the at least one sensor is selected from sensors for: oxygen levels (regional and systemic), glucose levels, glomerular filtration rate (GFR), blood pressure (BP), heart rhythm, cancer marker levels: alpha-fetoprotein, CA125, CA15-3, CA19-9, CEA, PSA, hCG or beta-hCG, hormone levels: insulin, glucagon, adrenaline, somatostatin, corticosteroids, thyroid hormones, leptin, adiponectin, histamine, sex hormones: testosterone, estrogen, progesterone, androstenedione, hypothalamic-pituitary agonists: TSH, ACTH, ADH (vaso and neurotransmitter levels: dopamine, serotonin, noradrenaline, acetylcholine, gamma aminobutyric acid (GABA), galanin, enkephalin, neuropeptide Y, opioids, endorphins, aspartic acid, D-serine, glutamic acid, glycine, nitric oxide, oxytocin, and medication levels: lithium, tricyclic antidepressants, antibiotics, antipsychotics, antiepileptics, anticancer drugs, and any combination thereof.

[0035] The invention further provides an implantable synthetic patch according to any one of the preceding claims for use in the diagnosis of at least one medical condition, disease, disorder or condition in a subject in need thereof.

[0036] The invention further provides a method of diagnosing at least one medical condition, disease, disorder or condition in a subject in need thereof, said method comprising the steps of providing an implantable synthetic patch according to any one of the preceding claims and implanting said implantable synthetic patch in said subject.

[0037] The invention further provides an implantable synthetic patch according to any one of the preceding claims for use in the treatment of at least one medical condition, disease, disorder or condition in a subject in need thereof; said implantable synthetic patch comprising at least one active agent (disclosed herein above and below).

[0038] The invention further provides a method of treating at least one medical condition, disease, disorder or condition in a subject in need thereof, said method comprising the steps of providing an implantable synthetic patch according to any one of the preceding claims, said implantable synthetic patch comprising at least one active agent (disclosed herein above and below), and implanting said implantable synthetic patch into said subject.

[0039] In some embodiments, the at least one medical condition, disease, disorder or condition is selected from diabetes, high blood pressure, arrhythmia, cancer, depression, drug addiction, hormone deficiency, menopause, mineral deficiency, osteoporosis, brain function, neurological disorders, inflammation, toxin levels, and the like, and any combination thereof.

[0040] In some embodiments, the implantable synthetic patch of the invention includes at least one receiver capable of receiving a signal enabling release of at least one active agent from the patch of the invention. In some embodiments, the release of the at least one active agent is a sustained release. In other embodiments, the release of the at least one active agent is a result of detection of at least one biological property by the sensor, reception of the transmission of a signal by an external receiving device (external to the patch of the invention), and reception of a signal for release of the at least one active agent by the at least one receiver of the patch of the invention.

[0041] The subject matter which is regarded as the invention is particularly pointed out and distinctly claimed in the concluding portion of the specification, however, the invention, both as to organization and method of operation, together with its objects, features, and advantages, may best be understood by reference to the following detailed description when read in conjunction with the accompanying drawings. [Brief description of the drawings]

[0042] [Figure 1] 1 illustrates an implantable sensor of the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0043] It will be appreciated that for simplicity and clarity of illustration, elements shown in the figures have not necessarily been drawn to scale. For example, dimensions of some of the elements may be exaggerated relative to other elements for clarity. Further, where considered appropriate, reference numerals may be repeated among the figures to indicate corresponding or analogous elements.

[0044] In the following detailed description, numerous specific details are set forth in order to provide a thorough understanding of the invention. However, it will be understood by those skilled in the art that the present invention may be practiced without these specific details. In other instances, well-known methods, procedures, and components have not been described in detail so as not to obscure the invention.

[0045] FIG. 1 shows an implantable sensor of the present invention (100) having an encapsulating / embedded porous polymer patch (103), a sensor (101), a WiFi and / or Bluetooth transmitter (102), a microprocessor (104), and a compartment containing an active agent (105).

[0046] Example 1 - Inventive coated RFID sensor - Subcutaneous implantation in rats Safety and performance evaluation of COAT RFID sensors in a rat model Study objective: To evaluate the safety and performance of RFID sensors coated with electrospun materials after subcutaneous implantation in SD rats.

[0047] Surgery: Each animal is subjected to a subcutaneous implantation in the dorsal flank region, where one side is implanted with a test device and the other side is implanted with a control device (uncoated RFID sensor). The implantation sites are marked with a tattoo or permanent marker.

[0048] Testing: Detailed individual clinical signs including local reactions at both implant sites: once per week. Body weights: once per week. Cageside observations: once per day including weekends. RFID reading of both implants - once per week.

[0049] Study period: 4 weeks

[0050] Post-operative care: Pain medication will be administered for up to 2 days after surgery (at the discretion of the designated veterinarian). Antibiotic prophylactic will be administered for up to 3 days after surgery (at the discretion of the designated veterinarian).

[0051] Final investigation: animals were euthanized, implanted sites were retrieved, and implant migration was recorded. The implanted devices were gently removed and immediately fixed in formalin solution (care was taken to avoid damaging the tissue-implant interface). Histopathological processing of all implanted sites: medial sectioning, paraffin embedding, and H&E staining (total, 12 slides).

[0052] Histopathological evaluation of all slides should include, but are not limited to, the extent of fibrosis / fibrous membrane and inflammation; degeneration as determined by changes in tissue morphology; severity and cell type of the inflammatory response; the presence and extent of necrosis; and other tissue changes such as vascularization, fatty infiltration, and granuloma formation.

Claims

1. An implantable synthetic patch comprising at least one porous polymer and at least one sensor and / or transmitter.

2. 10. The implantable synthetic patch of claim 1 having a porous polymer structure with pores less than 5 microns.

3. 10. The implantable synthetic patch of claim 1, having a porous polymer structure with pores between 5 and 20 microns.

4. 10. The implantable synthetic patch of claim 1 which is a biocompatible patch.

5. The implantable synthetic patch of any one of claims 1 to 3, which is a biodegradable patch.

6. The implantable synthetic patch of any one of claims 1 to 3, which is a non-biodegradable patch.

7. 10. The implantable synthetic patch of any one of the preceding claims, having a thickness of 50 to 250 microns.

8. 10. The implantable synthetic patch of any one of the preceding claims, having a thickness of 250 to 2500 microns.

9. 20. The implantable synthetic patch of any one of the preceding claims, wherein the porous polymer structure comprises nanofibers.

10. 20. The implantable synthetic patch of any one of the preceding claims, wherein the porous polymer structure comprises at least one porous electrospun polymer.

11. The porous polymer structure may be any of aromatic polyurethanes, polycarbonates, poly(DTE carbonate), polycaprolactone (PCL), polylactic acid (PLA), poly-L-lactic acid (PLLA), poly(DL-lactide-co-caprolactone, poly(ethylene-co-vinyl acetate), vinyl acetate, poly(methyl methacrylate), poly(propylene carbonate), poly(vinylidene fluoride), polyacrylonitrile, polycaprolactone, polycarbomethylsilane, polylactic acid, polystyrene, polyvinylpyrrolidone, polyvinyl alcohol (PVA), polyethylene oxide (PE), polyvinyl chloride (PCL), polyvinyl chloride (PCT ...

10. The implantable synthetic patch of any one of the preceding claims, comprising at least one polymer selected from polyvinyl chloride (PVC), hyaluronic acid (HA), chitosan, alginate, polyhydroxybutyrate and its copolymers, nylon 11, cellulose acetate, hydroxyapatite, poly(3-hydroxybutyrate-co-3-hydroxyvalerate), poly(DL-lactide), polycaprolactone, and poly(L-lactide) or any combination thereof.

12. 13. The implantable synthetic patch of any one of the preceding claims, further comprising at least one active agent.

13. 13. The implantable synthetic patch of claim 12, wherein the at least one active agent is selected from a protein, collagen, fibronectin, or TGF-β2, heparin, a growth factor, an antibody, an antimetabolite, a chemotherapeutic agent, an anti-inflammatory agent, an antibiotic agent, an antimicrobial agent, and any combination thereof.

14. 13. The implantable synthetic patch according to any one of the preceding claims, which is a transdermal patch.

15. The implantable synthetic patch of any one of the preceding claims, wherein the at least one sensor is a biosensor.

16. The at least one sensor may monitor oxygen levels (regional and systemic), glucose levels, glomerular filtration rate (GFR), blood pressure (BP), heart rhythm, cancer marker levels: alpha fetoprotein, CA125, CA15-3, CA19-9, CEA, PSA, hCG or beta hCG, hormone levels: insulin, glucagon, adrenaline, somatostatin, corticosteroids, thyroid hormones, leptin, adiponectin, histamine, sex hormones: testosterone, estrogen, progesterone, androstenedione, hypothalamic-pituitary agonists: TSH, ACTH, ADH (vasopressin), LH, FSH, GH, TRH (thyrotropin releasing hormone), 13. The implantable synthetic patch of any one of the preceding claims, selected from sensors for GnRH (Gonadotropin Releasing Hormone), GHRH (Growth Hormone Releasing Hormone), CRH (Corticotropin Releasing Hormone) and neurotransmitter levels: Dopamine, Serotonin, Noradrenaline, Acetylcholine, Gamma Aminobutyric Acid (GABA), Galanin, Encephalin, Neuropeptide Y, Opioids, Endorphins, Aspartic Acid, D-Serine, Glutamic Acid, Glycine, Nitric Oxide, Oxytocin, and drug levels: Lithium, Tricyclic Antidepressants, Antibiotics, Antipsychotics, Antiepileptics, Anticancer drugs and any combination thereof.

17. 13. The implantable synthetic patch of any one of the preceding claims for use in diagnosing at least one medical condition, disease, disorder or condition in a subject in need thereof.

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