Over the past five years, the University of Connecticut together with its start-up spin-off corporation (Biorasis Inc.) has been developing a totally implantable biosensor platform (0.5 mm x 0.5 mm x 5 mm) capable of continuously monitoring glucose. The underlying principle in developing this miniaturized sensor hinges on extreme miniaturization utilizing light, both as a powering source and a communication link. Such implant size reduction results in minimal tissue damage during implantation. The localized release of various tissue response modifiers has also afforded effective inflammation control and fibrosis suppression along with neo-angiogenesis. While significant progress has been achieved in the electrochemical determination of D-glucose using the highly-specific glucose oxidase enzyme, changes in user physiology (i.e. exercise, irregular homeostatis, anoxia/hypoxia, diet etc.) contribute to interferences that lower sensor accuracy. Objective/Hypothesis: By outfitting our implantable glucose sensing platform with two additional sensing elements capable of independently assessing oxygen and various interfering agent levels, the accuracy and reliability of glucose detection can be significantly improved, which will take us, a step closer to developing a closed-loop artificial pancreas. Study Design: We propose to develop a low-bias glucose+O2 sensing element (which is devoid of interference from endogenous redox-active species) and integrate it with two other (already-developed) sensing elements to accurately determine subcutaneous glucose concentrations irrespective of user physiology. This will be accomplished by outfitting the implantable platform with two additional potentiostats and an optically-coded, sensor-select circuit to sequentially interrogate each of the three sensing elements. All sensing elements and associated electrical and optical components will be integrated in a compact unit (0.75 x 0.75 x 9 mm) that is hermetically sealed against body fluids to enable long-term in vivo operation. This will be augmented by the respective optimization of the biocompatible sensor coatings to address the slightly enlarged sensor size, and develop in vitro release testing methods necessary for future FDA filing. Phase-II will focus on: (i) reducing the size of the multi-sensor unit, (ii) optimizing device assembly, and (iii) conducting extensive preclinical animal studies along with developing appropriate analytical methods necessary for FDA filing. Relevance: In view of the growing number of diabetics worldwide, there is a tremendous need for devices that provide accurate detection of glucose levels. In lieu of the difficulties associated with glucose monitoring using non-invasive methods, extreme miniaturization of a totally implantable device together with assured accuracy and long-term operation, present a viable alternative. The proposed multi-sensor platform addresses miniaturization and accurate glucose readings. In addition, the wireless communication and prolonged lifetime render it an effective device for diabetic care as well as a powerful tool for testing new drugs in small animals.
Public Health Relevance: The increasing occurrence of diabetes (ca. 23.6 and 189 million diabetic patients in US and rest of the world, respectively) poses a serious health problem, especially when associated with obesity, renal failure and other serious conditions. Continuous glucose monitoring will provide the necessary warning to prevent hypo- and hyper-glycemic events as well as to minimize fluctuations in glucose levels that would otherwise lead to many debilitating complications associated with diabetes. Currently, there is no totally implantable device for continuous glucose monitoring available on the market. Therefore, diabetics must rely on either finger pricking (approximately five times per day) or microprobe, skin-penetrating devices that need to be replaced every 3-7 days due to their open-wound nature and associated negative tissue responses. A reliable, long-term, continuous monitoring is expected to provide the necessary corrective feedback to the patient so that together with appropriate insulin delivery, an effective sugar-level management can be attained to prevent hypo- and hyper-glycemic events. The proposed research intends to realize the first generation of a low-cost, miniaturized, implantable sensor that can continuously and accurately monitor blood glucose levels over a period of one month. This implantable sensor will establish a wireless link to a wrist-watch-like communicator capable of interacting with various digital accessories (such as, personal digital assistants, cell phones and personal computers). The implanted device can be inserted under the skin and similarly removed via a needle, thus avoiding the need for surgical implantation and removal. Another important feature of this sensor is its ability to delineate interferences and accurately obtain glucose levels, independent of user physiology (exercise, irregular homeostatis, anoxia/hypoxia, diet etc.). The miniaturized size of this sensory platform has immediate applicability not only in diabetes management, but also to diabetes research, where the ability of obtaining continuous glucose monitoring of the smallest research animals (i.e. mice, rats) will provide an invaluable tool in diabetes drug development.
Public Health Relevance Statement: PROJECT NARRATIVE The increasing occurrence of diabetes (ca. 23.6 and 189 million diabetic patients in US and rest of the world, respectively) poses a serious health problem, especially when associated with obesity, renal failure and other serious conditions. Continuous glucose monitoring will provide the necessary warning to prevent hypo- and hyper-glycemic events as well as to minimize fluctuations in glucose levels that would otherwise lead to many debilitating complications associated with diabetes. Currently, there is no totally implantable device for continuous glucose monitoring available on the market. Therefore, diabetics must rely on either finger pricking (approximately five times per day) or microprobe, skin-penetrating devices that need to be replaced every 3-7 days due to their open-wound nature and associated negative tissue responses. A reliable, long-term, continuous monitoring is expected to provide the necessary corrective feedback to the patient so that together with appropriate insulin delivery, an effective sugar-level management can be attained to prevent hypo- and hyper-glycemic events. The proposed research intends to realize the first generation of a low-cost, miniaturized, implantable sensor that can continuously and accurately monitor blood glucose levels over a period of one month. This implantable sensor will establish a wireless link to a wrist-watch-like communicator capable of interacting with various digital accessories (such as, personal digital assistants, cell phones and personal computers). The implanted device can be inserted under the skin and similarly removed via a needle, thus avoiding the need for surgical implantation and removal. Another important feature of this sensor is its ability to delineate interferences and accurately obtain glucose levels, independent of user physiology (exercise, irregular homeostatis, anoxia/hypoxia, diet etc.). The miniaturized size of this sensory platform has immediate applicability not only in diabetes management, but also to diabetes research, where the ability of obtaining continuous glucose monitoring of the smallest research animals (i.e. mice, rats) will provide an invaluable tool in diabetes drug development.
NIH Spending Category: Assistive Technology; Bioengineering; Diabetes; Nutrition; Prevention
Project Terms: (11Beta,16alpha)-9-fluoro-11,17,21-trihydroxy-16-methylpregna-1,4-diene-3,20-dione; 1-Dehydro-16alpha-methyl-9alpha-fluorohydrocortisone; 16Alpha-methyl-9alpha-fluoro-1,4-pregnadiene-11beta,17alpha,21-triol-3,20-dione; 16Alpha-methyl-9alpha-fluoro-delta1-hydrocortisone; 16Alpha-methyl-9alpha-fluoroprednisolone; 1H-Purine-2,6,8(3H)-trione, 7,9-dihydro-; 2,6,8-Trihydroxypurine; 9Alpha-fluoro-11beta,17alpha,21-trihydroxy-16alpha-methylpregna-1,4-diene-3,20-dione; 9alpha-Fluoro-16alpha- methylprednisolone; APAP; Aacidexam; Abscission; Acetamide, N-(4-hydroxyphenyl)-; Acetamidophenol; Acetaminophen; Acetominophen; Address; Adexone; Aknichthol Dexa; Alba-Dex; Alin; Alin Depot; Alin Oftalmico; Ambene; Amplidermis; Anemul mono; Animal Experimental Use; Animal Experimentation; Animal Research; Animals; Anoxia; Antimicotico; Aquapred; Area; Artificial Pancreas; Ascorbic Acid; Attention; Auxiloson; Azona; Back; Baycuten; Baycuten N; Be element; Be++ element; Beryllium; Biocompatible; Biosensor; BlackBerry Device; Blood Glucose; Blood Sugar; Blood Vessels; Blueberry Device; Body Fluids; Body Tissues; Caring; Catalase A; Catheters; Cell Communication and Signaling; Cell Phone; Cell Signaling; Cells; Cellular Phone; Chemicals; Code; Coding System; Common Rat Strains; Communication; Connecticut; Corrosion; Corrosions; Corson; Cortidexason; Cortisumman; D-Glucose; Decacort; Decadrol; Decadron; Decalix; Decameth; Decasone R.p.; Dectancyl; Deenar; Dekacort; Deltafluorene; Deronil; Desamethasone; Desameton; Detection; Development; Development and Research; Devices; Dex-4; Dexa-Mamallet; Dexa-Rhinosan; Dexa-Scheroson; Dexa-sine; Dexace; Dexacortal; Dexacortin; Dexafarma; Dexafluorene; Dexalocal; Dexamecortin; Dexameth; Dexamethasone; Dexamethasonum; Dexamonozon; Dexapos; Dexinoral; Dexone; Dextrose; Diabetes Mellitus; Diet; Diffusion; Dinormon; Dorsum; Drugs; Electrodes; Electronics; Elements; Ensure; Enzymes; Event; Excision; Exercise; Exercise Physiology; Exercise, Physical; Exhibits; Extirpation; Feedback; Fibrosis; Fingers; Fluoro-9alpha Methyl-16alpha Prednisolone; Fluorodelta; Foreign Bodies; Fortecortin; Frequencies (time pattern); Frequency; Future; GFAC; Gammacorten; Generations; Glucose; Growth Agents; Growth Factor; Growth Factors, Proteins; Growth Substances; H2O2; Health; Hexadecadrol; Hexadrol; Humulin R; Hydrogels; Hydrogen Oxide; Hydrogen Peroxide; Hydrogen Peroxide (H2O2); Hydrogen-peroxide[{..}]hydrogen-peroxide oxidoreductase; Hydroperoxide; Hydroxyacetanilide; Hypoxia; Hypoxic; INFLM; Illumination; Image; Immune; Immune response; Implant; In Vitro; Individual; Inflammation; Insulin; Insulin (ox), 8A-L-threonine-10A-L-isoleucine-30B-L-threonine-; Insulin, Regular; Intellectual Property; Intracellular Communication and Signaling; Kidney Failure; Kidney Insufficiency; Knowledge; L-Ascorbic Acid; Lead; Legal patent; Licensing; Light; Lighting; Link; Liquid substance; Logic; Lokalison-F; Loverine; Mammals, Mice; Mammals, Rats; Marketing; Measures; Medication; Membrane; Methods; Methylfluorprednisolone; Mice; Microbeads; Microcid; Microdialysis; Microspheres; Millicorten; Miniaturisations; Miniaturization; Miniaturizations; Modeling; Molecular Weight; Monitor; Monosaccharides; Murine; Mus; Mymethasone; N-(4-Hydroxyphenyl)acetanilide; N-Acetyl-p-aminophenol; Nature; Needles; Novolin R; O element; O2 element; Obesity; Ocasa; Operation; Operative Procedures; Operative Surgical Procedures; Optics; Orgadrone; Oxidation-Reduction; Oxygen; Oxygen Deficiency; PDA Computer; Palm Pilot; Palm-top; Palm-top computer; Palmtop; Palmtop computer; Paracetamol; Patents; Patients; Pb element; Performance; Personal Computers; Personal Digital Assistant; Personal Digital Assistant Computer; Pharmaceutic Preparations; Pharmaceutical Preparations; Phase; Photoradiation; Physicians' Offices; Physiologic; Physiologic pulse; Physiological; Physiology; Pocket PCs; Pocket Personal Computer; Power Sources; Power Supplies; Predni-F; Pregna-1,4-diene-3,20-dione, 9-fluoro-11,17,21-trihydroxy-16-methyl-, (11beta,16alpha)-; Process; Pulse; R & D; R&D; Radiation; Rat; Rattus; Reaction; Reading; Redox; Removal; Renal Failure; Renal Insufficiency; Research; Research Design; Rest; Sensory; Side; Signal Transduction; Signal Transduction Systems; Signaling; Site; Skin; Source; Specificity; Spersadex; Spersadox; Staging; Study Type; Surgical; Surgical Interventions; Surgical Procedure; Surgical Removal; Telephone, Cellular; Tensile Strength; Testing; Time; Tissues; Trioxopurine; Universities; Uric Acid; VIT C; Variant; Variation; Visumetazone; Vitamin C; Water; Wireless Technology; Work; Wrist; adiposity; analytical method; angiogenesis; auricularum; base; beta-D-Glucose[{..}]oxygen 1-oxidoreductase; biological signal transduction; biomedical implant; catalase; commercialization; corpulence; corpulency; corpulentia; cost; cross-link; crosslink; diabetes; diabetes management; diabetic; diabetic patient; digital; dosage; drug development; drug/agent; fluid; glucose meter; glucose monitor; glucose oxidase; glucose sensor; heavy metal Pb; heavy metal lead; host response; hypodermic needle; imaging; immunoresponse; implant device; implantable device; implantation; improved; in vivo; indwelling device; liquid; membrane structure; millimeter; miniaturize; novel; obese; obese people; obese person; obese population; open wound; oxidation; oxidation reduction reaction; p-Acetamidophenol; p-Hydroxyacetanilide; pre-clinical; preclinical; prevent; preventing; public health relevance; ray (radiation); research and development; resection; response; seal; sensor; sensor (biological); study design; subcutaneous; sugar; surgery; tool; vascular; wireless
