Patent Publication Number: US-2021189450-A1

Title: Ethylene Oxide Absorption Layer for Analyte Sensing and Method

Description:
CROSS REFERENCE TO RELATED APPLICATION 
     This application does not claim priority from any other application. 
     TECHNICAL FIELD 
     The subject matter of this application pertains to detection and concentration of analytes in mammals. More particularly, the subject matter relates to the sterilization of analyte sensors for use within a mammal. 
     BACKGROUND OF THE DISCLOSURE 
     Mammals are known to have cellular sensors that self-detect chemical constituents of the body, in particular tissues or blood, so that the body can control changes in constituent concentrations. However, disease and pathophysiological states can impart deviations from normal concentrations of constituents in bodily tissues and blood. Techniques are known for detecting blood glucose levels associated with diabetes. Further similar bodily malfunctions are also desired to be detected so that therapy and diagnostics can be implemented for patients. However, further improvements are needed to increase accuracy and longevity of inserted sensors when measuring constituents and physical membrane lamination and permeability issues can negatively affect performance. 
     Ethylene oxide (ETO) has been known to be a low temperature sterilant. However, improvements are needed in order to further protect the sterilization and operation of cellular sensors, or biosensors. 
     SUMMARY 
     A sensor sterilization absorption layer is provided for increasing sensing performance when measuring analytes, such as glucose, in the body of mammals that improves reliability and useable life over previously known techniques. A sterilization absorption layer is provided on a sensing element containing high density of functional groups able to bind ethylene oxide. 
     In one aspect, an analyte biosensor is provided having an analyte biosensing layer and an ethylene oxide absorption layer. The ethylene oxide absorption layer is provided over the analyte biosensing layer. 
     In another aspect, an analyte biosensing assembly is provided having an analyte biosensing layer and a sterilization absorption layer. The sterilization absorption layer is provided over the analyte biosensing layer. 
     In yet another aspect, a method is provided for sterilizing a biosensor. The method includes: providing an analyte biosensing layer and a sterilization absorption layer over the analyte biosensing layer; exposing the sterilization absorption layer to organic compounds comprising one of enzymes and proteins; and binding ethylene oxide with the sterilization absorption layer. 
     These and other aspects are contemplated and described herein. It will be appreciated that the foregoing summary sets out representative aspects of a system and method for detecting releasable coupling of a cap with an insulin delivery device and assists skilled readers in understanding the following detailed description. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1  is a diagrammatic cross-sectional view of an analyte biosensor having a sterilization absorption layer over an analyte biosensing layer. 
         FIG. 2  is a diagrammatic cross-sectional view of an analyte biosensor with a non-ethylene oxide binding layer over an analyte biosensing layer, 
         FIG. 3  is a simplified diagrammatic representation of an ethylene oxide (ETO) binding mechanism to glucose oxidase for a biosensor. 
         FIG. 4  is a diagrammatic plot of median calibration ratios of glucose concentration over sensor signal for both thin and thick glucose oxidase (GOx) layers both with and without a sterilization absorption layer. 
         FIG. 5  is a plot of low, medium and high absorption layer mechanisms of electrochemical impedance (capacitance) versus frequency for a biosensor with no exposure to ethylene oxide (ETO). 
         FIG. 6  is a plot of low, medium and high absorption layer mechanisms of electrochemical impedance (capacitance) versus frequency for a biosensor with exposure to ethylene oxide (ETO). 
         FIG. 7  is a simplified diagrammatic representation of an ethylene oxide (ETO) sterilization for a biosensor having a binding mechanism to an absorption layer for glucose oxidase. 
     
    
    
     DETAILED DESCRIPTION OF THE EMBODIMENTS 
     This disclosure is submitted in furtherance of the constitutional purposes of the U.S. Patent Laws “to promote the progress of science and useful arts” (Article 1, Section 8). 
       FIG. 1  is a diagrammatic cross-sectional view of an analyte biosensor  10  having a sterilization absorption layer  12  over an analyte biosensing layer  14 , according to one implementation. More particularly, according to one implementation, the sterilization absorption layer  12  comprises an ethylene oxide (ETO) binding layer  13  and a non-ethylene oxide binding layer  24  having a layer thickness, X 1 . The analyte biosensing layer  14  comprises a glucose oxidase (GOx) layer  15  comprising a deactivated glucose oxidase (GOx) layer  18  and an active glucose oxidase (GOx) layer  20 . Sterilization absorption layer  12  enables passage of an interstitial fluid comprising a glucose and oxygen (O 2 ) mixture  26  through ethylene oxide (ETO) binding layer  13  from an in vivo exposure to tissue and/or bloods constituents where ethylene oxide  22  binds to ethylene oxide (ETO) binding layer  13  within sterilization absorption layer  12 . Glucose and oxygen mixture  26  passes through a relatively thin deactivated glucose oxidase (GOx) layer  18  and into an active glucose oxidase (GOx) layer  20  where sensor  10  detects an electrical current that is proportional to the quantity of active glucose oxidase. Such detected capacitance change is provided below in further detail with reference to  FIGS. 6 and 7  which enables detection of a specific biosensing state, or condition in such tissue and/or blood. 
     As shown in  FIG. 1 , analyte biosensing layer  14  includes a glucose oxidase (GOx) layer  15  comprising a relatively thin deactivated glucose oxidase (GOx) layer  18  proximate layer  12  and a relatively thick glucose oxidase (GOx) layer  20  beneath deactivated layer  18 . Layer  20  is deposited atop a platinum layer, or surface  16 . Optionally, any other suitable material, or metal layer, such as gold can be utilized in place of a platinum layer. 
     As detailed in  FIG. 1 , sterilization layer  12  and analyte biosensing layer  14  can be constructed with other optional components for sterilization layers and analyte biosensing layers including enzyme-based analyte sensing layers configured to detect one of: glucose, ketone, and lactate. 
     Such enzyme-based analyte sensing layer shown in  FIG. 1  can be configured to realize glucose assay biosensing and comprises one of: glucose oxidase, glucose dehydrogenase, a modification of glucose oxidase, and a modification of glucose dehydrogenase. Such enzyme-based analyte sensing layer can be configured to realize ketone assay biosensing comprising 3-hydroxybutyrate dehydrogenase. Further, such enzyme-based analyte sensing layer can be configured to realize lactate assay biosensing comprising lactate dehydrogenase. 
     Such analyte biosensing layer of  FIG. 1  can comprise a non-enzyme-based analyte sensing layer configured to detect glucose. Such non-enzyme-based analyte sensing layer can be configured to realize glucose assay biosensing comprising a boronic acid hydrogel. 
     Such ethylene oxide absorption layer of  FIG. 1  can comprise a sterilization absorption layer over the analyte biosensing layer configured to preserve analyte sensing performance of the underlying ethylene oxide absorption layer. Such ethylene oxide absorption layer can also comprise a polymer with one of: a repeating amine; and one of a carboxyl acid group. Such ethylene oxide absorption layer can further also comprise one of: poly-1-lysine; chitosan, polyethyleneimine, and a protein (HSA). 
     Additionally, an adhesive layer can be provided at least in part by the ethylene oxide absorption layer, or binding layer  13  (of  FIG. 1 ). As shown in  FIG. 2 , the ethylene oxide absorption layer itself can also provide the function of adhesion for layers  114  and  124 . 
     Analyte biosensor  10  of  FIG. 1  provides an analyte biosensing assembly including an analyte biosensing layer  14  and a sterilization layer  12  over the analyte biosensing layer  14 . Such analyte biosensing layer of  FIG. 1  can comprise an enzyme-based analyte sensing layer configured to detect one of: glucose, ketone, and lactate. Such sterilization absorption layer can comprise an ethylene oxide absorption layer comprising a high density of functional groups configured to bind with ethylene oxide. In such case, the functional groups can comprise a polymer with one of: a repeating amine; and one of a carboxyl acid group. Such sterilization absorption layer can comprise one of: poly-1-lysine; chitosan, polyethyleneimine, and a protein (HSA). Such sterilization absorption layer can comprise one of: linear molecules, branched molecules and dendrimer molecules. Such sterilization absorption layer can further comprise an adhesive layer. Such sterilization absorption layer can comprise a first region having a first thickness and a second region having a second thickness unique from the first thickness. Finally, such sterilization absorption layer can be provided with a thickness that provides a metering layer configured to control rate of transmission of analyte to the analyte biosensing layer. 
     Also according to  FIG. 1 , a method is provided for sterilizing a biosensor. The method includes: providing an analyte biosensing layer and a sterilization absorption layer over the analyte biosensing layer; exposing the sterilization absorption layer to organic compounds comprising one of enzymes and proteins; and binding ethylene oxide with the sterilization absorption layer. In one case, the analyte biosensing layer comprises an enzyme-based analyte sensing layer, and further comprising detecting at the analyte biosensing layer one of: glucose, ketone, and lactate. In one case, the sterilization absorption layer comprises an ethylene oxide absorption layer comprising a high density of functional groups configured to bind with ethylene oxide, and further comprising binding ethylene oxide with the functional groups. In such case, the functional groups can comprise a polymer with one of: a repeating amine; and one of a carboxyl acid group. 
       FIG. 2  is a diagrammatic cross-sectional view of an analyte biosensor  110  with a non-ethylene oxide binding layer  124  over an analyte biosensing layer  114 , according to a non-preferred implementation. More particularly, non-ethylene oxide binding layer  124  is layered over analyte biosensing layer  114  comprising a glucose oxidase (GOx) layer  115  having a substantially thick deactivated glucose oxidase (GOx) layer  118  and into an active glucose oxidase (GOx) layer  120 . Due to a lack of an ethylene oxide binding layer (such as layer  12  of  FIG. 1 ), ethylene oxide  122  binds to glucose oxidase layer  118  which causes such deactivation and reduces accuracy of detected current changes in sensor  110  as activated glucose oxidase layer  120  is reduced in thickness over that shown in the implementation of  FIG. 1 . Non-ethylene oxide binding layer  124  has a layer thickness X 2  where X 1  is greater than X 2  due to the addition of an ETO-binding layer. 
     As a result of the reduced thickness of activated glucose oxidase layer  120 , sensor  120  is less able to accurately detect current by breaking down products generated by layer  120 .  FIGS. 6 and 7  below a different technique to measure the effort of ethylene oxide on protective/absorption layer that enables detection of a specific biosensing state, or condition in such tissue and/or blood. Layer  112  enables passage of a glucose and oxygen (O 2 ) mixture  26  through non-ethylene oxide binding layer  124  from an in vivo exposure to tissue and/or blood constituents where ethylene oxide  122  binds to glucose oxidase  118  in layer  114 , causing deactivation. In operation, sensor  120  detects current by breaking down the products generated by layer  120 . Therefore, if layer  120  is thinner or compromised, the current does not enable as accurate a detection of a specific biosensing state. Passage of glucose and oxygen mixture  26  into a thinner active glucose oxidase (GOx) layer  120  where sensor  120  detects an impedance, or capacitance as provided below in further detail with reference to  FIGS. 6 and 7  does not enable as accurate a detection of a specific biosensing state, or condition in such tissue and/or blood. Layer  120  is deposited atop a platinum layer, or surface  116 , but can optionally be provided atop a gold layer, or some other suitable metal layer. 
       FIG. 3  is a simplified diagrammatic representation of an ethylene oxide (ETO) binding mechanism  30  for binding to a glucose oxidase layer for a biosensor of  FIG. 2  that does not have an absorption layer. More particularly, a first stage or step involves an ethylene oxide (ETO) sterilization Step  32 . Secondly, ethylene oxide (ETO) binds to an absorption layer in step  34 . Subsequently, an enzyme deactivation step  36  occurs which results in a decreased in layer  114  comprising layer  118  being deactivated. This deactivation of layer  118  results in a decreased signal with glucose  38  as shown in Step  38 . Finally, an increased calibration ration is shown in Step  40  resulting from the enzyme deactivation of a portion  118  of the sensing layer provided by layer  114 . 
       FIG. 4  is a diagrammatic plot of median calibration ratios of glucose concentration over sensor signal for both thin and thick glucose oxidase (GOx) layers both with and without a sterilization absorption. Column A shows individual value plot of median calibration ratio for high oxygen concentration, medium oxygen concentration, and low oxygen concentration where there is a thin GOx layer and no protective layer over a sensor. Column B shows the same where there is a thin GOx layer and a protective layer over a sensor. Column C shows the same where there is a thick GOx layer and no protective layer over a sensor. Finally, Column D shows the same where there is a thick GOx layer and a protective layer over a sensor. The Median Calibration Ratio represents a ratio of the “glucose concentration” over the “sensor signal” that is detected as shown in  FIG. 4 . 
       FIGS. 5 and 6  result from an experiment using a sensor having a different sensor structure than that shown in  FIGS. 1 and 2 . More particularly, this sensor structure had an ETO binding layer (see layer  12 , with a height of X 1 ) that was deposited onto a metal surface (see layer  16 , with the material actually being gold). This tested sensor structure had three levels of height/thickness of layer  12  deposited onto layer  16 .  FIGS. 5 and 6  then compare the effect of ETO on layer  12 . Essentially, this “electrical impedance” technique provides an actual proof of ETO binding to layer  12 , by changing the resulting electrical impedance signature drastically. In essence,  FIGS. 5 and 6  utilize this different sensor embodiment in order to support assertions made regarding  FIGS. 1 and 2 . 
       FIG. 5  is a plot of low, medium and high absorption layer mechanisms of electrochemical impedance (capacitance) versus frequency for a biosensor of  FIG. 2  with exposure to ethylene oxide and having exposure to ethylene oxide (ETO) because there is no sterilization absorption layer. 
       FIG. 6  is a plot of low, medium and high absorption layer mechanisms of electrochemical impedance (capacitance) versus frequency for a biosensor of  FIG. 1  with no exposure of ethylene oxide (ETO) where there is an ethylene oxide (ETO) binding layer that provides a protective layer. The sterilization absorption layer comprises an ETO binding layer which provides a protective layer over the biosensor. 
       FIG. 7  is a simplified diagrammatic representation of an ethylene oxide (ETO) sterilization process  40  for a biosensor having a binding mechanism to an absorption layer for glucose oxidase. More particularly, ethylene oxide (ETO) sterilization Step  42  precedes Step  44  where ETO binds to an absorption layer  12  (see  FIG. 1 ). Step  44  depicts ETO  22  (see  FIG. 1 ) bound to sterilization absorption layer  22 . Subsequently, the resulting capacitance of the sterilization absorption layer  22  (see  FIG. 1 ) decreases in Step  46 . Subsequently, the impedance (or capacitance) Z imag  changes due to the layer changing. As shown in  FIG. 5 , the absorption layer significantly changes capacitance with addition of the ETO absorption layer. 
     Pursuant to the process summarized in  FIG. 7 , the ethylene oxide absorption layer protects the underlying analyte biosensing layer. This underlying analyte biosensing layer may be enzyme based and/or non-enzyme based. Analytes include glucose, ketone, and lactate. Enzyme biosensing layer include examples such as glucose oxidase and/or glucose dehydrogenase and/or modification thereof for glucose assay biosensing for 1 st  generation, 2 nd  generation and 3 rd  generation biosensing. Other enzyme biosensing layers include examples such as 3-hydroxybutyrate dehydrogenase and lactate dehydrogenase for ketone assay and lactate assay sensing. Non-enzyme biosensing layers include examples such as boronic acid hydrogels for glucose assay. 
     Ethylene oxide (ETO) creates alkylation reactions with organic compounds such as enzymes and other proteins. These reactions inactivate enzymes having sulfhydryl groups providing an effective sterilizing agent for both heat sensitive and moisture sensitive materials. 
     As shown in  FIG. 4 , provision of a sterilization absorption layer is configured to preserve analyte sensing performance from ethylene oxide. Analyte sensing can be glucose-based and/or other enzyme-based sensing platforms. The sterilization absorption layer is configured to contain high density of functional groups that are able to bind ethylene oxide, as shown in  FIG. 5 . Provision of a sterilization absorption layer comprised of a polymer with repeating amine and/or carboxylic acid groups is shown in  FIG. 5  with a significantly decreased capacitance values for each range of layer thickness. The sterilization absorption layer can be poly-1-lysine, chitosan, polyethyleneimine, or proteins such as HSA. The sterilization absorption layer can be linear, branched, dendrimer. The material can act as both an adhesive layer and a sterilization absorption layer. Finally, the sterilization absorption layer can be different made with different thicknesses. 
     The terms “a”, “an”, and “the” as used in the claims herein are used in conformance with long-standing claim drafting practice and not in a limiting way. Unless specifically set forth herein, the terms “a”, “an”, and “the” are not limited to one of such elements, but instead mean “at least one”. 
     While the subject matter of this application was motivated in addressing a glucose biosensor encasement, it is in no way so limited. The disclosure is only limited by the accompanying claims as literally worded, without interpretative or other limiting reference to the specification, and in accordance with the doctrine of equivalents. Other aspects and implementations of other biosensor encasements are contemplated. 
     In compliance with the statute, the various embodiments have been described in language more or less specific as to structural and methodical features. It is to be understood, however, that the various embodiments are not limited to the specific features shown and described, since the means herein disclosed comprise disclosures of putting the various embodiments into effect. The various embodiments are, therefore, claimed in any of its forms or modifications within the proper scope of the appended claims appropriately interpreted in accordance with the doctrine of equivalents.