Control of biofouling in implantable biosensors

• US 9,101,301 B2
• Filed: 08/15/2012
• Issued: 08/11/2015
• Est. Priority Date: 08/15/2011
• Status: Active Grant

• Current Assignee: Biorasis Incorporated, University of Connecticut (State of Connecticut)
• Original Assignee: University of Connecticut (State of Connecticut)
• Inventors: Papadimitrakopoulos, Fotios, Vaddiraju, Santhisagar
• Primary Examiner(s): Ball, J. Christopher
• Application Number:
  US13/586,436
• Publication Number:
  US 20130213110A1
• Time in Patent Office: 1,091 Days
• Field of Search: 422422-426, 422484-488, 20440301-40315, 605/908, 605/910
• US Class Current: 1/1
• CPC Class Codes: A61B 2562/18 Shielding or protection of sensors from environmental influences, e.g. protection from mechanical damage
• CPC Class Codes: A61B 2562/247 Hygienic covers, i.e. for covering the sensor or apparatus during use
• CPC Class Codes: A61B 5/145 Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissuemeasuring of blood pressure or blood flow A61B5/02; non-radiation detecting or locating of foreign bodies in blood A61B5/06
• CPC Class Codes: A61B 5/14503 invasive, e.g. introduced into the body by a catheter or needle or using implanted sensors A61B5/1459, A61B5/1464, A61B5/1473, A61B5/1482, A61B5/14865 take precedence
• CPC Class Codes: A61B 5/1459 invasive, e.g. introduced into the body by a catheter A61B5/1464 takes precedence
• CPC Class Codes: A61B 5/14865 invasive, e.g. introduced into the body by a catheter or needle or using implanted sensors
• CPC Class Codes: A61B 5/1495 Calibrating or testing of in-vivo probes
• CPC Class Codes: C12Q 1/001 Enzyme electrodes
• CPC Class Codes: G01N 33/52 Use of compounds or compositions for colorimetric, spectrophotometric or fluorometric investigation, e.g. use of reagent paper and including single- and multilayer analytical elements immunological elements G01N33/54386; involving labelled immunochemicals G01N33/58; for haemoglobin or occult blood G01N33/72

Abstract

Disclosed herein is a device comprising a biosensor having disposed upon it a coating; the coating comprising a polymer matrix; where the polymer matrix is operative to facilitate the inwards and outwards diffusion of analytes and byproducts to and from the sensing element of the biosensor; and a sacrificial moiety; the sacrificial moiety being dispersed in the polymer matrix, where the sacrificial moiety erodes with time and increases the porosity of the polymer matrix thus offsetting decreases in analyte permeability as a result of biofouling.

Claims

1. A device comprising:

a biosensor having disposed upon it a coating;

the coating comprising;

a polymer matrix;

where the polymer matrix is operative to facilitate an inwards and outwards diffusion of analytes, byproducts and other water soluble entities towards a sensing element of the biosensor; and

a sacrificial moiety;

the sacrificial moiety being dispersed in the polymer matrix, where the sacrificial moiety erodes with time and increases the porosity of the polymer matrix thus offsetting decreases in analyte permeability as a result of biofouling,

where the polymer matrix comprises hydrogels, xerogels, organogels, absorbent polymers, dip-coated or layer-by-layer coated polyelectrolytes, electropolymerized polymers, or combinations thereof.

2. The device of claim 1, where the erosion of sacrificial moieties creates a new implantable device-tissue interface;

the new implantable device-tissue interface presenting a fresh surface to biofouling media to re-establish analyte transport within the polymeric matrix.

3. The device of claim 1, where the polymeric matrix experiences a ‘

partial’

or ‘

no’

collapse following the erosion of the sacrificial moieties.

4. The device of claim 1, where the sacrificial moieties comprise a biodegradable polymer.

5. The device of claim 4, where the biodegradable polymer is a polyanhydride, polyaspirin, polylactic-glycolic acid, poly-caprolactone, copolymers of polylactic-glycolic acid and poly-caprolactone, polyhydroxy-butyrate-valerate, polyorthoester, polyethylene oxide-butylene terephthalate, poly-D,L-lactic acid-p-dioxanone-polyethylene glycol block copolymer, or a combination thereof.

6. The device of claim 1, where the sacrificial moiety comprises an amphiphilic block copolymer.

7. The device of claim 1, where the amphiphilic block copolymer comprises a hydrophilic block and a hydrophobic block;

the hydrophilic block being selected from the group consisting of polyacrylates, polyacrylamides, polyvinylacetates, polyvinyl acetamides, polyvinyl alcohols, neutralized and un-neutralized polymeric acids, neutralized and un-neutralized polyacrylics acids, neutralized and un-neutralized polysulfonic acids, neutralized and un-neutralized polystyrene sulfonic acids, polydiallyl dimethyl ammonium chlorides, poly(l-glycerol methacrylate)s, poly(2-dimethylaminoethyl methacrylate)s, poly(2-ethyl-2-oxazoline), poly(2-hydroxyethyl methacrylate/methacrylic acid)s, poly(2-hydroxypropyl methacrylate)s, poly(2-methacryloxyethyltrimethylammonium halide)s, poly(2-vinyl-1-methylpyridinium halide)s, poly(2-vinylpyridine N-oxide)s, poly(2-vinylpyridine)s, poly(3-chloro-2-hydroxypropyl-2-methacryloxyethyldimethylammonium chloride)s, polysaccharides, derivatives of polysaccharides, hydroxyethyl guar, carboxymethyl guar, carboxyethyl guar, carboxymethyl hydroxypropyl guar, cellulose, cellulose derivatives, derivatives of cellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, carboxyethylcellulose, carboxymethyl hydroxyethyl cellulose, carboxymethyl hydroxypropyl cellulose, karaya, locust bean, pectin, tragacanth, acacia, carrageenan, alginates, salts of alginate, propylene glycol alginate, agar, gellan, xanthan, scleroglucan, and a combination thereof and the hydrophobic block being selected from the group consisting of polyacetals, polyolefins, polycarbonates, polystyrenes, polyesters, polyamides, polyamideimides, polyarylates, polyarylsulfones, polyethersulfones, polyphenylene sulfides, polyvinyl chlorides, polysulfones, polyimides, polyetherimides, polytetrafluoroethylenes, polyetherketones, polyether etherketones, polyether ketone ketones, polybenzoxazoles, polyphthalides, polyacetals, polyanhydrides, polyvinyl ethers, polyvinyl thioethers, polyvinyl ketones, polyvinyl halides, polyvinyl nitriles, polyvinyl esters, polysulfonates, polysulfides, polythioesters, polysulfones, polysulfonamides, polyureas, polyphosphazenes, polysilazanes, polyethylene terephthalate, polybutylene terephthalate, polyurethane, polytetrafluoroethylene, polychlorotrifluoroethylene, polyvinylidene fluoride, polyoxadiazoles, polybenzothiazinophenothiazines, polybenzothiazoles, polypyrazinoquinoxalines, polypyromellitimides, polyquinoxalines, polybenzimidazoles, polyoxindoles, polyoxoisoindolines, polydioxoisoindolines, polytriazines, polypyridazines, polypiperazines, polypyridines, polypiperidines, polytriazoles, polypyrazoles, polypyrrolidines, polycarboranes, polyoxabicyclononanes, polydibenzofurans, polyphtalides, polyacetals, polyanhydrides, polyvinyl ethers, polyvinyl thioethers, polyvinyl ketones, polyvinyl halides, polyvinyl nitriles, polyvinyl esters, polysulfonates, polysulfides, polythioesters, polysulfones, polysulfonamides, polyureas, polyphosphazenes, polysilazanes, polysiloxanes, polyolefins, and a combination thereof.

8. The device of claim 1, where the erosion of the sacrificial moieties occurs when exposed to physiological fluids.

9. The device of claim 1, where the erosion of the sacrificial moieties occurs by localized heat, changes in pH, light irradiation, ultrasound, or combinations thereof.

10. The device of claim 9, where said changes in pH are achieved by cleaving N-tert-butoxycarbonyl-based derivatives (t-BOC derivatives) present in the said sacrificial moieties.

11. The device of claim 1, where the sacrificial moieties are colloidosomes comprising a biodegradable polymeric bead or a labile group, wherein an inner hollow core is surrounded by hydrophobic bead like structures.

12. The device of claim 1, where the said sacrificial moieties are polymersomes comprising a biodegradable polymeric bead.

13. The device of claim 12, where the polymersomes contain nano- or micro-crystals within their outer shell.

14. The device of claim 12, where the polymersomes have an outer shell that is a biodegradable hydrophobic polymer and the inner core is a dried hydrophilic polymer.

15. The device of claim 1, where the coating increases porosity in proportion to a decrease in permeability from the said biofouling.

16. The device of claim 12, where the polymersome have an outer shell that comprises a biodegradable hydrophobic polymer and an inner core that comprises a dried hydrophilic polymer.

17. The device of claim 12, where the said polymersomes contain an assortment of polymer-coated reactive species within their shell that release gases upon degradation of polymersomes.

18. The device of claim 1, where the sacrificial moieties are selected from the group consisting of polymersomes, colloidosomes, polymeric microspheres, block copolymers, interpenetrating networks, filled composites, polymer coated nanoparticles, nanoplatlets, nanorods, polymer coated salt crystals, self-assembled polymer spheres, and combinations thereof.

19. A method of manufacturing a biosensor comprising:

disposing a coating on a biosensor;

the coating comprising;

a polymer matrix;

where the polymer matrix is operative to facilitate an inwards and outwards diffusion of analytes and byproducts to and from the sensing element of the biosensor; and

a sacrificial moiety;

the sacrificial moiety being dispersed in the polymer matrix, where the sacrificial moiety erodes with time and increases the porosity of the polymer matrix thus offsetting decreases in analyte permeability as a result of biofouling,

where the polymer matrix comprises hydrogels, xerogels, organogels, absorbent polymers, dip-coated or layer-by-layer coated polyelectrolytes, electropolymerized polymers, or combinations thereof.

20. An analyte-sensing device capable of reliable sensing in a biofouling-prone media comprising:

a sensing element;

a self sealing layer disposed on the sensing element capable of allowing diffusion of electro-active species towards the sensing element;

where the self sealing layer is not prone to swelling and is intimately bonded to the sensing element;

one or more layers comprising enzymes that are disposed upon the self-sealing layer;

selectively the enzymes being operative to convert an analyte of interest to an electro-active species;

where the electro-active species diffuses through the self sealing layer to produce a detectable signal proportional to a concentration of the analyte;

a second layer disposed upon the one or more layers that comprises enzymes;

the second layer being operative to limit diffusion of the analyte and control diffusion towards the sensor of molecules with size larger than that of the analyte;

a third layer comprising a composite coating that comprises a polymer matrix and a sacrificial moiety;

where the polymer matrix is operative to facilitate the inwards and outwards diffusion of analytes and byproducts to and from the sensing element; and

wherein the sacrificial moiety is dispersed in the polymer matrix, where the sacrificial moiety erodes with time and increases the porosity of the polymer matrix thus offsetting decreases in analyte permeability as a result of biofouling.

21. The device of claim 20, where the electro-active specie is one of H₂O₂, OH⁻

, H⁺, O₂ and NO.

22. The device of claim 21, where the sensing element is a working electrode of an electrochemical sensor.

23. The device of claim 22, where the said sensing element senses a change in one or more of amperometric, potentiometric, voltammetry, optical, magnetic, piezoelectric, electronic, piezostrictive, magnetostrictive, electromagnetic, photonic, or impedance changes.

24. A method to realize an internal self-calibration of an implantable biosensor, the biosensor comprising:

two sensing elements;

where self calibration of the biosensor is achieved through differential measurement of background currents obtained from the two sensing elements;

where one of the sensing elements is encased in an outer composite membrane, while the other of the said sensing element is intentionally left blank;

the said outer composite membrane comprises a polymer matrix and a sacrificial moiety;

where the polymer matrix is operative to facilitate an inwards diffusion of analytes towards the sensing element; and

wherein the sacrificial moiety is dispersed in the polymer matrix, where the sacrificial moiety erodes with time and increases the porosity of the polymer matrix thus offsetting decreases in analyte permeability as a result of biofouling,

where the polymer matrix comprises hydrogels, xerogels, organogels, absorbent polymers, dip-coated or layer-by-layer coated polyelectrolytes, electropolymerized polymers, or combinations thereof.

25. A device comprising:

a biosensor having disposed upon it a coating;

the coating comprising;

a polymer matrix;

where the polymer matrix is operative to facilitate an inwards and outwards diffusion of analytes, byproducts and other water soluble entities towards a sensing element of the biosensor; and

a sacrificial moiety;

the sacrificial moiety being dispersed in the polymer matrix, where the sacrificial moiety erodes with time and increases the porosity of the polymer matrix thus offsetting decreases in analyte permeability as a result of biofouling,

where the erosion of the sacrificial moieties occurs by localized heat, changes in pH, light irradiation, ultrasound, or combinations thereof, and said changes in pH are achieved by cleaving N-tert-butoxycarbonyl-based derivatives (t-BOC derivatives) present in the said sacrificial moieties.

26. A method of manufacturing a biosensor comprising:

disposing a coating on a biosensor;

the coating comprising;

a polymer matrix;

where the polymer matrix is operative to facilitate an inwards and outwards diffusion of analytes and byproducts to and from the sensing element of the biosensor; and

a sacrificial moiety;

the sacrificial moiety being dispersed in the polymer matrix, where the sacrificial moiety erodes with time and increases the porosity of the polymer matrix thus offsetting decreases in analyte permeability as a result of biofouling,

where the erosion of the sacrificial moieties occurs by localized heat, changes in pH, light irradiation, ultrasound, or combinations thereof, and said changes in pH are achieved by cleaving N-tert-butoxycarbonyl-based derivatives (t-BOC derivatives) present in the said sacrificial moieties.

27. A method to realize an internal self-calibration of an implantable biosensor, the biosensor comprising:

two sensing elements;

where self calibration of the biosensor is achieved through differential measurement of background currents obtained from the two sensing elements;

where one of the sensing elements is encased in an outer composite membrane, while the other of the said sensing element is intentionally left blank;

the said outer composite membrane comprises a polymer matrix and a sacrificial moiety;

where the polymer matrix is operative to facilitate an inwards diffusion of analytes towards the sensing element; and

wherein the sacrificial moiety is dispersed in the polymer matrix, where the sacrificial moiety erodes with time and increases the porosity of the polymer matrix thus offsetting decreases in analyte permeability as a result of biofouling,

where the erosion of the sacrificial moieties occurs by localized heat, changes in pH, light irradiation, ultrasound, or combinations thereof, and said changes in pH are achieved by cleaving N-tert-butoxycarbonyl-based derivatives (t-BOC derivatives) present in the said sacrificial moieties.