Patent Application
20200158679
Embodiments of the subject matter described herein relate generally to sensors for measuring analyte concentrations. More particularly, embodiments of the subject matter relate to biosensors having an extended lifetime.
Needle-implantable biosensors have shown to be useful for continuous analyte monitoring applications, such as glucose monitoring applications for use in diabetes management.
Some needle-implantable glucose biosensors operate by monitoring the amount of H2O2 which is produced from the catalyzed reaction of glucose by GOx to gluconic acid and H2O2 in the following reaction steps:
The product H2O2 is then electrochemically oxidized on the working electrode surface of a probe of the biosensor, thereby generating an electrical current response signal to be measured. The blood glucose concentration can be correlated to the current response signal obtained from the oxidation of the H2O2, or to the electrochemical reduction of O2, via the reversible reaction:
One prevalent type of biosensor is a biosensor that forms part of a transcutaneous system, and which measures subcutaneous interstitial glucose. Most biosensors of this type have FDA approval for a 3- to 7-day window of use. After this time, biosensors may become less accurate, due to, for example, biofouling of the sensor, which causes a decrease in the sensitivity of the biosensor.
Biofouling is a mechanism where sensor probes, at insertion, become exposed to blood, interstitial fluid, and blood borne- and interstitial fluid borne- constituents. When the sensor probe is exposed to these bodily-fluid borne- constituents, the sensor will become “fouled” with a layer of blood plasma proteins, adhered blood cells and glucose-consuming inflammatory cells, amongst other pollutants. This form of fouling is typically the first stage in the body's “foreign body response”. Subsequent stages of foreign body response may include capsulation of the sensor probe.
Biofouling typically decreases the diffusion of interstitial glucose to the sensor, thereby artificially decreasing the glucose concentration in the area surrounding the sensor probe. As such, the biosensor may detect an erroneous too-low amount of glucose, thereby leading to an incorrect glucose value being measured and shown to the user.
The typical time for a conventional sensor probe to become biofouled to the point where the sensitivity of the biosensor decreases to an unacceptable level is around 7 days. At this point, it is necessary for the user to change the biosensor, which may cause the user discomfort.
Accordingly, it is desirable to extend the lifespan of implanted biosensor probes.
Furthermore, other desirable features and characteristics will become apparent from the subsequent detailed description and the appended claims, taken in conjunction with the accompanying drawings and the foregoing technical field and background.
This summary is provided to introduce a selection of concepts in a simplified form that are further described below in the detailed description. This summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used as an aid in determining the scope of the claimed subject matter.
According to a first exemplary embodiment, there is provided a sensor probe for a biosensor. The sensor probe includes a base substrate; and a plurality of electrode sets overlying the base substrate. Each set of the plurality of electrode set is individually operable for measuring an analyte concentration value when the probe is implanted in a patient. The probe also includes a biodegradable coating covering at least one electrode set of the plurality of electrode sets, wherein the biodegradable coating does not cover at least one other electrode set of the plurality of the electrode sets.
According to a second exemplary embodiment, there is provided a biosensor. The biosensor includes a sensor probe for a biosensor. The sensor probe includes a base substrate; and a plurality of electrode sets overlying the base substrate. Each set of the plurality of electrode set is individually operable for measuring an analyte concentration value when the probe is implanted in a patient. The probe also includes a biodegradable coating covering at least one electrode set of the plurality of electrode sets, wherein the biodegradable coating does not cover at least one other electrode set of the plurality of the electrode sets. The biosensor further includes an impulse generator, and wherein the biodegradable coating is operably connected to the impulse generator, the impulse generator operable to generate an impulse for initiating degradation of the biodegradable coating.
According to a third exemplary embodiment, there is provided a method of manufacturing a probe for a biosensor, the method includes the step of providing a base substrate. The method also includes the step of forming a plurality of electrode sets on the base substrate. The method also includes the step of covering at least one electrode set of the plurality of electrode sets with a biodegradable coating, whilst not covering at least one other electrode set of the plurality of electrode sets with the biodegradable coating.
According to a fourth exemplary embodiment, there is provided a method of operating a biosensor including a sensor probe for a biosensor. The sensor probe includes a base substrate; and a plurality of electrode sets overlying the base substrate. Each set of the plurality of electrode set is individually operable for measuring an analyte concentration value when the probe is implanted in a patient. The probe also includes a biodegradable coating covering at least one electrode set of the plurality of electrode sets, wherein the biodegradable coating does not cover at least one other electrode set of the plurality of the electrode sets. The method includes the step of obtaining, using the at least one first electrode set, analyte concentration measurements. The method also includes the step of assessing, using a processor, an extent of biofouling of the at least one first electrode set of the plurality of electrode sets. The method also includes the step of comparing, using a processor the determined extent of biofouling to a pre-determined threshold. The method also includes the step of generating, using an impulse generator, an impulse operable to initiate degradation of the biodegradable coating and, after degradation of the biodegradable coating. The method also includes the step of obtaining, using the at least one second electrode set, analyte concentration measurements.
A more complete understanding of the subject matter may be derived by referring to the detailed description and claims when considered in conjunction with the following figures, wherein like reference numbers refer to similar elements throughout the figures.
and
The following detailed description is merely illustrative in nature and is not intended to limit the embodiments of the subject matter or the application and uses of such embodiments. As used herein, the word “exemplary” means “serving as an example, instance, or illustration.” Any implementation described herein as exemplary is not necessarily to be construed as preferred or advantageous over other implementations. Furthermore, there is no intention to be bound by any expressed or implied theory presented in the preceding technical field, background, brief summary or the following detailed description.
As shown in
In an exemplary embodiment, the probe 26 further includes a catalyst which stimulates the reaction of blood glucose to gluconic acid and H2O2, which H2O2, may be used to determine glucose concentration in the manner described above. In some exemplary embodiments, insulin may be administered via the insulin infusion device 34 based on the determined blood glucose concentration.
In exemplary embodiments, the probe includes multiple electrode sets. A biodegradable coating (not shown in
Turning to
Although the electrodes shown in each electrode set 142, 143, 144, 145, 146 of
Although
At least one of the electrode sets 142, 143, 144, 145, 146 is covered with a biodegradable coating (not shown in this figure). At least one of the electrode sets 142, 143, 144, 145, 146 is not covered with the biodegradable coating. Multiple electrode sets may be covered with different thicknesses of biodegradable coating, as shall be explained in more detail below.
The function of the biodegradable coating will now be explained with reference to
The working electrode WE2, counter electrode CE2 and reference electrode RE2 of the electrode set 143 is covered with a biodegradable coating 400. The working electrode WE1, counter electrode CE1 and reference electrode RE1 of the other electrode set 142 of the electrode sets 142, 143 is not covered with a biodegradable coating 400, such that these electrodes are exposed to bodily fluids when implanted into tissue of a user.
In use, when the probe 26 is implanted into a user, glucose measurements are performed using the electrode set 142 which is not covered by the biodegradable coating 400. In other words, a voltage is applied to the working electrode WE1 of the electrode set 142 which is not covered with the biodegradable coating 400, and the current response is measured in a conventional manner.
The first electrode set 142 operates for a first time period, for example a number of days, before biofouling of the electrodes decreases the sensitivity of the biosensor to such an extent that the glucose concentrations measured by this electrode set 142 become inaccurate. For example, the first electrode set 142 may be operable for a period of seven days.
Whilst the first electrode set 142 is operating, the biodegradable coating 400 covering the second electrode set 143 gradually degrades, as represented in the middle drawing of
The thickness of the biodegradable coating 400 is selected such that the time taken for the coating to fully degrade corresponds to the time taken for the first electrode set 142 to become inoperative or inaccurate due to biofouling. As such, after this time period and full degradation of the coating 400, the second electrode set 143 is then exposed to the blood and interstitial fluid of the user and may then be used in the monitoring of glucose concentration levels of the user. This is represented in the bottom drawing of
As such, the service lifespan of the sensor probe 26 of
In exemplary embodiments, the biodegradable coating is formed from a polymer made up of hydrophobic or hydrophilic blocks, or a combination of hydrophilic and hydrophobic blocks. For example, the hydrophobic, biodegradable blocks can be comprise of one or more of: Poly (lactic-co-glycolic acid), poly (lactic acid), Poly Glycolic acid, polyanhydrides, polyaspirins, etc. as well as combinations thereof. The hydrophilic blocks may be composed of one or more of poly vinyl alcohol, polyethylene oxide, polybetaines, polyacrylates, polyacrylamides, polyvinylacetates, etc. as well as combinations thereof.
In an exemplary embodiment, the molecular weight and thickness of the biodegradable coating can be varied such that the rate of degradation of the biodegradable coating matches the rate of biofouling of the sensors. The rate of biofouling of the sensors can be estimated by calculating the mean drop in sensor sensitivity over a population of multiple sensors over a fixed period of time and at a fixed glucose concentration. On the basis of this estimated rate of biofouling, the molecular weight and thickness of the biodegradable coating can be selected during formation of the biodegradable coating.
In the above-described embodiments, the biodegradable coating degrades naturally in vivo.
In alternative exemplary embodiments, a stimulus may be applied to the biodegradable coating in order to stimulate degradation of the coating at a specific time. In exemplary embodiments, as shown in
The biodegradable coating 400 degrades in response to the impulse generated by the impulse generator 500. In this manner, the degradation of the biodegradable coating 400 can be initiated when desired to allow for the coated electrode set 143 to begin glucose concentration measurements when an uncoated electrode set 142 is biofouled to such an extent that it no longer has the required degree of sensitivity. In an exemplary embodiment, a user may transmit a signal to the impulse generator 500 to generate an impulse to degrade the coating 400. Alternatively, the impulse generator 500 may automatically generate an impulse after a pre-determined time period (which time period may be determined in the same manner as described above) to degrade the coating 400.
Turning to
At Step S62, a plurality of electrode sets are formed on the at least one base substrate. In embodiments, the plurality of electrode sets are formed by depositing a conductive material, for example platinum, onto the at least one base substrate and then forming electrode sets using this conductive material. In exemplary embodiments, the conductive material is deposited onto the at least one base substrate by sputtering or electroplating the conductive material onto the base substrate. In exemplary embodiments, the electrode sets are formed by etching or laser ablating the conductive material deposited onto the at least one base substrate. The method then progresses to step S63.
At Step S63, a biodegradable coating is formed over at least one electrode set of the plurality of electrode sets. In an exemplary embodiment, the biodegradeable coating is deposited over the electrode set by slot coating followed by patterning using photolithography. In an alternative exemplary embodiment, the biodegradable coating is deposited by slot coating over a pre-laid mask which can be later removed. In exemplary embodiments, the biodegradable coating is poly lactic glycolic acid. The method then may optionally progress to step S64.
In optional Step S64, an impulse generator is operably connected to the biodegradable coating such that an impulse generated by the impulse generator is operable to initiate degradation of the biodegradable coating.
At step S71, a first set of electrodes are used to obtain analyte concentration measurements.
The analyte of interest may be glucose. Concurrently, the extent of biofouling of the first set of electrodes is assessed. In exemplary embodiments, the extent of biofouling of the first set of electrodes is assessed by determining the time over which the electrodes have been exposed to blood and interstitial fluid. In alternative exemplary embodiments, the extent of biofouling of the first set of electrodes is assessed by looking at rate of change of the signal at a fixed glucose concentration and comparing it to a pre-determined look-up charts which tabulates the rate of signal change to changes in the electrode set or outer membrane. The method then progresses to step S72.
At step S72 a determination is made, using a processor, as to whether the extent of biofouling of the first electrode set has exceeded a pre-determined amount. In exemplary embodiments, this determination is made by comparing, using a processor, whether the first set of electrodes has been exposed to blood and interstitial fluid for a time longer than a pre-determined time. In exemplary embodiments, this determination is made by electronically comparing, using a processor, the rate of change of the signal to a pre-determined look-up chart. The processor may form part of an impulse generator or may be a separate component included in the biosensor. If, on the basis of this determination, it is determined that the extent of biofouling of the first electrode set is less than the pre-determined amount, the method reverts to Step S71. If, on the basis of this determination, it is determined that the extent of biofouling of the first electrode set is greater than the pre-determined amount, the method then progresses to step S73.
At step S73, an impulse is generated, using an impulse generator, and imparted to a biodegradable coating covering a second electrode set to initiate degradation of the biodegradable coating and thereby expose the second electrode set. After the biodegradable coating is degraded, the method progresses to step S74.
At step S74, the second set of electrodes are used to obtain analyte concentration measurements.
In addition, certain terminology may also be used in the following description for the purposes of reference only, and thus are not intended to be limiting. For example, terms such as “upper”, “lower”, “above”, and “below” refer to directions in the drawings to which reference is made. Terms such as “front”, “back”, “rear”, “side”, “outboard”, and “inboard” describe the orientation and/or location of portions of the component within a consistent but arbitrary frame of reference which is made clear by reference to the text and the associated drawings describing the component under discussion. Such terminology may include the words specifically mentioned above, derivatives thereof, and words of similar import. Similarly, the terms “first”, “second”, and other such numerical terms referring to structures do not imply a sequence or order unless clearly indicated by the context.
For the sake of brevity, conventional techniques related to biosensor probe manufacturing may not be described in detail herein. Furthermore, the connecting lines shown in the various figures contained herein are intended to represent exemplary functional relationships and/or physical couplings between the various elements. It should be noted that many alternative or additional functional relationships or physical connections may be present in an embodiment of the subject matter.
While at least one exemplary embodiment has been presented in the foregoing detailed description, it should be appreciated that a vast number of variations exist. It should also be appreciated that the exemplary embodiment or embodiments described herein are not intended to limit the scope, applicability, or configuration of the claimed subject matter in any way. Rather, the foregoing detailed description will provide those skilled in the art with a convenient road map for implementing the described embodiment or embodiments. It should be understood that various changes can be made in the function and arrangement of elements without departing from the scope defined by the claims, which includes known equivalents and foreseeable equivalents at the time of filing this patent application.
