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Cited by 347Polymer Surface Interaction StudiesDiabetes Management and ResearchElectrochemical sensors and biosensors

Biocompatible Materials for Continuous Glucose Monitoring Devices

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Nichols, Scott P., Koh, Ahyeon, Storm, Wesley L., Shin, Jae Ho, Schoenfisch, Mark H.·2013·Chemical Reviews
DOI 10.1021/cr300387jPMC PMC3624030
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Abstract

ADVERTISEMENT RETURN TO ISSUEPREVReviewNEXTBiocompatible Materials for Continuous Glucose Monitoring DevicesScott P. Nichols†, Ahyeon Koh†, Wesley L. Storm†, Jae Ho Shin‡, and Mark H. Schoenfisch*†View Author Information† Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States‡ Department of Chemistry, Kwangwoon University, Seoul, Korea*Address: Chemistry Department of Chemistry, University of North Carolina at Chapel Hill, CB#3290, Chapel Hill, North Carolina, 27599, USA. Tel: +1 (919) 843-8714. Fax: +1 (919) 962-2388. E-mail: [email protected]Cite this: Chem. Rev. 2013, 113, 4, 2528–2549Publication Date (Web):February 7, 2013Publication History Received19 September 2012Published online7 February 2013Published inissue 10 April 2013https://pubs.acs.org/doi/10.1021/cr300387jhttps://doi.org/10.1021/cr300387jreview-articleACS PublicationsCopyright © 2013 American Chemical SocietyRequest reuse permissionsArticle Views8353Altmetric-Citations268LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Anatomy,Carbohydrates,Inflammation,Peptides and proteins,Sensors Get e-Alerts

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  • Premisecitation

    Near-infrared spectroscopy allows 90-95% of light to pass through the stratum corneum and epidermis into subcutaneous space with minimal tissue adsorption independent of skin pigmentation.

    “Optical detection of glucose via near infrared (NIR) spectroscopy enables 90–95% of the light to pass through the human stratum corneum and epidermis into subcutaneous space with minimal tissue adsorption independent of skin pigmentation.19,40–41”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [19] Vaddiraju S., 2010, J. Diabetes Sci. Technol. source

      Not checked in the free run.

    • cites [40] Pickup J., 1999, BMJ source

      Not checked in the free run.

    • cites [41] Tura A., 2007, Diabetes Res. Clin Pract. source

      Not checked in the free run.

  • Premisecitation

    CGM supplies real-time data on glucose trends, magnitude, duration, and frequency of daily fluctuations.

    “Continuous glucose monitoring (CGM) provides real-time information on trends (i.e., whether the glucose levels are increasing or decreasing), magnitude, duration, and frequency of glucose fluctuations during the day.5–6”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [5] Heller A., 1999, Annu. Rev. Biomed. Eng. source

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    • cites [6] Wilson G. S., 2000, Chem. Rev. source

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  • Premisecitation

    A subcutaneous sensor using differential oxygen detection with glucose oxidase and catalase achieved accurate glucose measurements for more than one year by correcting for oxygen reduction differences.

    “Accurate glucose measurements were carried out for >1 year by taking into account the difference in oxygen reduction at an electrode producing a glucose-modulated current and a reference electrode producing an oxygen-dependent current.31”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [31] Gough D. A., 2010, Sci. Transl. Med. source

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  • Premisereasoning

    Percutaneous sensors require frequent calibration, about twice daily, even after stabilization because sensor response changes.

    “Frequent calibration (e.g., 2 times per day) is required even after the stabilization period due to changes in sensor response.”
    Quote in the paperNot a substantial claim
  • Interpretationcitation

    The subcutaneous nature of fully implanted sensors likely reduced micromotion effects associated with the foreign body response.

    “The subcutaneous nature of the sensors likely minimized any micromotion effects associated with the foreign body response.32”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] Helton K. L., 2011, J. Diabetes Sci. Technol. source

      Not checked in the free run.

  • May combine two claims. 93
  • Classified as probably not a substantial claim. 15
  • The quote only partly states this claim. 1

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    Premisenone given

    Continuous iontophoretic current causes skin erythema and irritation.

    “However, the continuous applied current causes skin erythema and irritation.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Photobleaching of fluorophores and tissue scattering are significant drawbacks of optical glucose detection.

    “Photobleaching of the fluorophore and scattering in tissue are significant drawbacks.19,35–36”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [19] Vaddiraju S., 2010, J. Diabetes Sci. Technol. source

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    • cites [35] Moschou E. A., 2004, J. Fluoresc. source

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    • cites [36] Pickup J. C., 2005, Biosens. Bioelectron. source

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  • May combine two claims.

    Premisenone given

    Fully subcutaneous enzyme-immobilized amperometric biosensors can be implanted for months to years, whereas percutaneous versions are used for less than one month.

    “Enzyme-immobilized amperometric biosensors have been implanted fully subcutaneously as CGM devices for extended periods (months to years) or percutaneously for <1 month.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Most electron mediators used in second-generation glucose biosensors are toxic, and mediator-oxygen competition persists.

    “Unfortunately, most mediators are toxic and competition between the mediator and oxygen still exists.19,22”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [19] Vaddiraju S., 2010, J. Diabetes Sci. Technol. source

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    • cites [22]

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    Premisecitation

    Microdialysis avoids direct sensor implantation, but in vivo glucose recovery is erratic because of the foreign body response.

    “Microdialysis avoids direct implantation of a sensor but the glucose measurement (i.e., recovery) remains erratic in vivo due to the foreign body response.19,24–25”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [19] Vaddiraju S., 2010, J. Diabetes Sci. Technol. source

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    • cites [24] Oliver N. S., 2009, Diabetic Med. source

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    • cites [25] Mou X., 2010, Biomaterials source

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    Premisecitation

    Sweating, often linked to hypoglycemia, alters glucose extraction rate and causes erroneous iontophoretic readings.

    “Additionally, sweating, often associated with hypoglycemia, affects the rate of extraction of glucose and therefore causes erroneous results when readings must be most accurate.29–30”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [29] Ferrante do Amaral C. E., 2008, Med. Eng. Phys. source

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    • cites [30] Vashist S. K., 2012, Anal. Chim. Acta source

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  • May combine two claims.

    Interpretationreasoning

    Enzyme-based electrochemical glucose biosensors have high selectivity and sensitivity, but their dynamic range is limited by oxygen availability.

    “Although enzyme-based electrochemical glucose biosensors are characterized with high selectivity and sensitivity due their enzymatic nature, the dynamic range of such sensors is limited by co-substrate (i.e., oxygen) availability.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Almost all invasive sensing devices have infection risks, discomfort, and analytical response problems related to the foreign body response.

    “Almost all invasive sensing devices are characterized by infection risks, discomfort, and analytical response issues related to the foreign body response (FBR).29–30”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [29] Ferrante do Amaral C. E., 2008, Med. Eng. Phys. source

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    • cites [30] Vashist S. K., 2012, Anal. Chim. Acta source

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    Premisecitation

    Miniaturization of optical glucose monitoring instrumentation is not currently possible, preventing personalized continuous monitoring devices.

    “Moreover, miniaturization of the instrumentation is not currently possible thus precluding personalized devices for continuous monitoring.19”
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    • cites [19] Vaddiraju S., 2010, J. Diabetes Sci. Technol. source

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    Premisereasoning

    Iontophoretic glucose sensors are non-invasive and less prone to fouling because skin filters large biomolecules.

    “Iontophoretic electrochemical sensors are not invasive and experience less fouling because of the skin’s ability to filter large biomolecules.”
    Quote in the paperNot a substantial claim

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    Premisereasoning

    Percutaneous needle-type microsensors have a shorter stabilization period than subcutaneous sensors but carry infection risk from penetrating the dermis.

    “Though such sensors typically are characterized as having a shorter stabilization period (e.g., 2–4 h) compared to subcutaneous glucose sensors, the device penetrates through an opening in the dermis with concomitant infection risk.”
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    Premisecitation

    Raman spectroscopy gives narrow and distinct peaks but requires long spectral acquisition and stabilization times.

    “While Raman spectroscopy gives narrow and distinct peaks (in contrast to NIR absorbance), long spectral acquisition and stabilization times are required.30”
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    • cites [30] Vashist S. K., 2012, Anal. Chim. Acta source

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    Premisecitation

    Optical glucose detection is sensitive and does not damage the host, but skin pigmentation and epidermal thickness can worsen analytical response.

    “While optical detection provides sensitive detection without damaging the host, skin pigmentation and epidermal thickness can negatively impact the analytical response among hosts.35–36”
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    • cites [35] Moschou E. A., 2004, J. Fluoresc. source

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    • cites [36] Pickup J. C., 2005, Biosens. Bioelectron. source

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    Premisecitation

    The electrode potential used to monitor hydrogen peroxide also oxidizes endogenous electroactive species and produces high current densities.

    “Additionally, the working electrode potential required to monitor hydrogen peroxide (i.e., ~+0.6 V vs. Ag/AgCl) will also oxidize electroactive endogenous species (e.g., ascorbic acid and acetaminophen) and create high current densities.19”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [19] Vaddiraju S., 2010, J. Diabetes Sci. Technol. source

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    Premisecitation

    Electrode fouling, or passivation, occurs when diffusible small molecules contact the electrode surface after penetrating the sensor membrane.

    “Electrode fouling (often called electrode passivation) is another cause of sensor instability, and occurs when diffusible small molecules come into contact with the surface of the electrode after penetration of the sensor membrane.74”
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    • cites [74] Wisniewski N., 2000, Colloid. Surface. B source

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    Premisecitation

    Long-term implanted glucose sensors in humans provided accurate readings while immobile, but posture changes led to erratic outputs.

    “For example, Gilligan et al. found that long-term implanted glucose sensors in humans provided accurate sensor readings while immobile, but posture changes (i.e., standing and/or moving) led to erratic outputs.85”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [85] Gilligan B. C., 2004, Diabetes Technol. Ther. source

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    Premisenone given

    Commercial CGM sensors are not intended as warning or prognostic devices but as tools to inform users and physicians about glucose trends.

    “However, these sensors are not intended as warning or prognostic devices but rather as tools to inform users and physicians of trends in glucose fluctuations.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Current numerical and clinical accuracy criteria for CGM include linear regressions and correlation coefficients, MAD and MARD, Clarke Error Grid Analysis, and ISO criteria.

    “Current numerical and clinical accuracy criteria for CGM includes linear regressions and correlation coefficients; mean (or median) absolute and relative absolute difference (MAD and MARD); Clarke Error Grid Analysis (Clarke EGA); and, International Standard Organization (ISO) criteria.76”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [76] Clarke W. L., 2007, J. Diabetes Sci. Technol. source

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    Premisenone given

    Changes in blood dielectric properties are not specific to glucose, leading to poor accuracy in impedance-based glucose measurements.

    “Unfortunately, the changes in blood dielectric properties are not specific to glucose, resulting in poor accuracy.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Subcutaneous oxygen tension in humans ranges from about 40 mm Hg to 130 mm Hg and is affected by anesthetics and hypoxia at the implantation site.

    “Subcutaneous oxygen tension for humans ranges from 40 mm Hg (~5 kPa) to 130 mm Hg (~17kPa) with partial pressures affected by anesthetics and hypoxia at the implantation site.70”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [70] Koschwanez H. E., 2007, Biomaterials source

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    Premisecitation

    Pressures as low as 2 kPa diminish blood flow near the skin, and 7 kPa completely occluded blood circulation in diabetic patients, whereas non-diabetics withstood up to 22 kPa before total blood occlusion.

    “Pressures as low as 2 kPa have been shown to diminish blood flow near the skin while only 7 kPa completely occluded blood circulation in diabetic patients whereas non-diabetics withstood pressures up to 22 kPa before total blood occlusion.88”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [88] Petrofsky J. S., 2011, J. Diabetes Sci. Technol. source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The continuous glucose-error grid comprises a point-error grid analysis for blood glucose measurement accuracy and a rate-error grid analysis for prediction capability.

    “Because CGM systems also provide information on glucose fluctuations, the continuous glucose-error grid (CG-EGA) has been introduced comprising of (1) a point-error grid analysis (P-EGA) that evaluates the sensor accuracy in terms of accurate blood glucose measurements; and, (2) a rate-error grid analysis (R-EGA) that assesses the prediction capability of the sensor.77”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [77] Kovatchev B. P., 2004, Diabetes Care source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Oxygen concentration in interstitial fluid is about ten times lower than glucose concentration, creating an oxygen deficit that is addressed by an outer diffusion-controlled membrane.

    “Oxygen concentration in interstitial fluid is approximately ten times lower than the concentration of glucose in interstitial fluid resulting in an “oxygen deficit” state that is addressed by an outer diffusion-controlled membrane.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    The analytical performance of CGM sensors changes drastically upon implantation, making methods for defining and assessing accuracy critical for clinical use.

    “Since the analytical performance of CGM sensors changes drastically upon implantation, methods for defining and assessing sensor accuracy are critical for clinical use.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Even with accurate calibration, repeated calibration is required because sensor sensitivity changes over time due to physiological fluctuations and the foreign body response.

    “Even with an accurate calibration, repeated calibration is required as the sensor sensitivity changes over time due to physiological fluctuations and the foreign body response to the sensor.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Since 1999, CGM systems have been FDA approved, but only percutaneously implanted electrochemical glucose sensors are currently sold in the United States.

    “Since 1999, CGM systems have been approved by the FDA but only percutaneously implanted electrochemical glucose sensors are currently for sale in the United States.53”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [53] Henning T., 2010

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  • May combine two claims.

    Premisenone given

    Electrochemical detection of hydrogen peroxide requires oxygen, which is a cofactor in the glucose oxidase reaction.

    “The electrochemical detection of hydrogen peroxide requires oxygen, a cofactor in the GOx enzymatic reaction.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Surface enhanced Raman spectroscopy dramatically shortens acquisition times and improves sensitivity and limit of detection.

    “Recent advances have demonstrated that surface enhanced Raman spectroscopy (SERS) dramatically decreases acquisition times with concomitant improvements in both sensitivity and limit of detection.45–46”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [45] Shafer-Peltier K. E., 2003, J. Am. Chem. Soc. source

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    • cites [46] Yonzon C. R., 2004, Anal. Chem. source

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  • May combine two claims.

    Premisereasoning

    FDA-regulated sensor lifetimes of 5-7 days require regular biosensor replacement, creating significant financial burden for patients.

    “Due to finite FDA-regulated sensor lifetimes (5–7 d), the biosensor must be replaced on a regular basis with significant financial burden on the individual patient.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    Empirical data suggest in vivo lag times of 10-15 min, indicating that angiogenesis has an integral function in early granulation tissue.

    “empirical data suggests that lag times range from 10–15 min in vivo, indicating the integral function of angiogenesis in early granulation tissue.”
    Quote in the paperNot a substantial claim

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    Interpretationcitation

    The reversibility seen after rinsing indicated that the process was passive and probably resulted from biofouling on the sensor.

    “Nevertheless, this reversibility indicated that the process was passive and likely caused by biofouling on the sensor.100”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [100] Thomé-Duret V., 1996, Diabetes Metab.

      Not checked in the free run.

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    Premisecitation

    Sensor lag time for native tissue was estimated at about 20 min, but tripled when modeled with reduced diffusion due to a capsule.

    “Sensor lag times for native tissue was estimated at ~20 min, but tripled when modeled with decreased diffusion due to a capsule.107”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [107] Sharkawy A. A., 1997, J. Biomed. Mater. Res. source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Macrophages serve three primary functions: host defense, wound healing, and immune regulation.

    “Indeed, macrophages serve three primary functions in the body: host defense, wound healing, and immune regulation.95”
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    • cites [95] Mosser D. M., 2008, Nat. Rev. Immunol. source

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    Premisecitation

    Injecting 10^4-10^5 mast cells at the implant site caused sensor performance to recover within about 15 min, followed by a decrease in glucose response after 1-2 days.

    “While glucose sensor performance recovered soon after injection (~15 min), the sensor response to glucose decreased after 1–2 days”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [106] Klueh U., 2010, Biomaterials source

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    Premisecitation

    The foreign body response can cause local pH to drop as low as 3.6, disrupting biosensor performance because glucose oxidase activity is pH dependent.

    “This process can result in a local pH’s dropping as low as 3.6 and disrupting biosensor performance as the activity of GOx is pH dependent.94”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [94] Zhao Q. H., 1993, J. Biomed. Mater. Res. source

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    Premisecitation

    In vivo glucose sensitivity peaked at day 7 and then decreased for the remainder of the study.

    “The glucose sensitivity in vivo peaked at day 7, but then decreased for the duration of the study.108”
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    • cites [108] Dungel P., 2008, J. Biomed. Mater. Res. Part A source

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    Premisecitation

    In mast cell-deficient mice, sensor performance was markedly better and remained reliable throughout the 28-day period.

    “Sensor performance in mast cell-deficient mice was markedly better with reliable sensor function throughout the 28-day period.106”
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    • cites [106] Klueh U., 2010, Biomaterials source

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    Interpretationcitation

    Microdialysis probes consume much more glucose than electrochemical glucose sensors and may therefore underestimate biofouling effects in vivo.

    “microdialysis probes consume significantly more glucose than electrochemical glucose sensors and therefore may underestimate the effects of biofouling in vivo.105”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [105] Lowry J. P., 1998, J. Neurochem. source

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    Premisecitation

    In the same study, rinsing improved the glucose response but did not restore it to pre-implantation levels.

    “response to glucose improved after rinsing, albeit not to pre-implantation levels.100”
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    • cites [100] Thomé-Duret V., 1996, Diabetes Metab.

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  • May combine two claims.

    Interpretationreasoning

    Collagen encapsulation persists for the lifetime of the device and negatively impacts sensor performance with respect to sensitivity and response, such as lag times.

    “The collagen encapsulation will persist for the lifetime of the device, negatively impacting sensor performance with respect to sensitivity and response (e.g., lag times).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Tecoflex SG-85A polyurethane membranes on needle-type glucose sensors in rats after 30 h provided the biocompatibility often seen with polyurethane and ensured ideal sensor performance by limiting glucose diffusion.

    “The Tecoflex SG-85A membrane provided the biocompatibility often observed with polyurethane while also ensuring ideal sensor performance by limiting glucose diffusion.34”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [137] Ward W. K., 2002, Biosens. Bioelectron. source

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    • cites [34] Bindra D. S., 1991, Anal. Chem. source

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  • May combine two claims.

    Premisecitation

    The physical properties of an implant, such as its size, affect the FBR, and the large size of the stainless steel cage will influence the overall immune response to the materials.

    “the physical properties of the implant (e.g., size) impact the FBR, and the large size of the stainless steel cage will influence the overall immune response to the materials.115”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [115] Ward W. K., 2002, Biomaterials source

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  • May combine two claims.

    Premisecitation

    At 20 months, capsules were thinner at the implant's corners, while the face closest to the skin had a thicker capsule than the opposite side.

    “At 20 months, thinner capsules were observed at the implant’s corners while the face of the implant closest to the skin had a thicker capsule than the opposite side.130”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [130] Li D. J., 1999, J. Biomed. Mater. Res. source

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    Premisecitation

    Histological analysis revealed delayed neovascularization and less matrix production in diabetic rabbits.

    “Histological analysis revealed delayed neovascularization and less matrix production in the diabetic rabbits”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [128] Gerritsen H., 2000, J. Biomed. Mater. Res. source

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  • May combine two claims.

    Premisecitation

    Subcutaneous implants had no blood vessels or collagen inside the porous material, while percutaneous experiments showed significant collagen and vascularization, indicating a differential FBR depending on whether the implant was purely subcutaneous or percutaneous.

    “While examination of the subcutaneous implant noted no blood vessels or collagen within the interior of the porous material, the percutaneous experiments revealed significant levels of collagen and vascularization, indicating a differential FBR dependent on the nature (i.e., purely subcutaneous vs. percutaneous) of the implant.121”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [121] Koschwanez H. E., 2008, J. Biomed. Mater. Res. Part A source

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    Premisecitation

    Human subcutaneous tissue had a high concentration of adipose cells, whereas rat tissue had larger amounts of collagen.

    “Histology samplings from human subcutaneous tissue showed a high concentration of adipose cells while rat tissue was characterized with larger amounts of collagen.126”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [126] Wisniewski N., 2002, Am. J. Physiol.-Endocrinol. Metab source

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  • May combine two claims.

    Interpretationcitation

    The increases in mass transfer in those simulations were not attributed to any specific part of the FBR and could arise from collagen capsule thickness, blood vessel density, or other unanticipated factors.

    “the increases to mass transfer were not attributed to any specific part of the FBR and could originate from collagen capsule thickness, blood vessel density, or other unanticipated factors.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [110] Jablecki M., 2000, Anal. Chem. source

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    Premisecitation

    The optical tissue window enables tissue monitoring and correlation with sensor performance.

    “The optical tissue window enables tissue monitoring and correlation to the sensor performance.116–118”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [116] Makale M. T., 2005, Am. J. Physiol.-Heart C source

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    • cites [117] Ertefai S., 1989, J. Biomed. Eng. source

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    • cites [118] Koschwanez H. E., 2008, J. Diabetes Sci. Technol. source

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  • May combine two claims.

    Premisecitation

    Nafion-coated CGM probes implanted in canines were functional for up to 10 days, but the membranes were unstable, with significant cracking and eventual failure.

    “Moussy et al. implanted Nafion-coated CGM probes into canines that proved functional for up 10 days, but ultimately the membranes were deemed unstable with significant cracking and eventual failure.122”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [122] Moussy F., 1994, Int. J. Artif. Organs source

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  • Classified as probably not a substantial claim.

    Interpretationcitation

    These results require caution when extrapolating results from animal models to humans.

    “Taken together, these results necessitate careful consideration and caution when extrapolating results from animal models to humans.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [126] Wisniewski N., 2002, Am. J. Physiol.-Endocrinol. Metab source

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    Premisecitation

    Textured surfaces elicited a more favorable FBR, and much of the response was attributed to differential shear stress from interaction between the textured surface and surrounding fatty tissue.

    “While textured surfaces elicited a more favorable FBR, much of the response that did occur was attributed to differential sheer stress caused by the interaction between the textured surface of the device and the surrounding fatty tissue.132”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [132] Picha G. J., 1996, J. Biomed. Mater. Res. source

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    Premisecitation

    Anesthesia is not required to observe tissue in real time, which matters because anesthesia can alter microvasculature circulation.

    “Anesthesia is not required to observe the tissue in real-time, an important consideration for glucose sensor performance correlation as anesthesia can alter microvasculature circulation.116”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [116] Makale M. T., 2005, Am. J. Physiol.-Heart C source

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  • May combine two claims.

    Interpretationcitation

    Temporary signal reductions may result from local tissue damage caused by forces exerted on the sensor and may be solved by using more flexible materials.

    “Therefore, temporary signal reductions may actually be the result of local tissue damage caused by forces exerted on the sensor and may be solved by using more flexible materials.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [133] Klueh U., 2011, J. Diabetes Sci. Technol. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationcitation

    These model results identify the histological parameters of key interest when assessing the biocompatibility of materials for glucose sensors.

    “the results do identify the histological parameters of key interest when assessing the biocompatibility of materials for glucose sensors.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [111] Novak M. T., 2010, Anal. Bioanal. Chem. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The Novak model concluded that collagen capsule thickness was the primary source of sensor lag time and had little impact on sensor response attenuation.

    “The model was ultimately used to conclude that collagen capsule thickness, a common histological parameter, was the primary source of sensor lag time with little impact on sensor response attenuation.111”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [111] Novak M. T., 2010, Anal. Bioanal. Chem. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    When the same materials were implanted percutaneously, histological differences were less apparent, with porous coatings giving a twofold increase in vascularization and a twofold increase in collagen content compared with bare sensors at 2 weeks.

    “when the same materials were implanted percutaneously, histological differences were less apparent, with porous coatings giving a twofold increase in vascularization and a twofold increase, rather than decrease, in collagen content compared to bare sensors at 2 weeks.121”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [121] Koschwanez H. E., 2008, J. Biomed. Mater. Res. Part A source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Jablecki and Gough's simulations concluded that increased mass transfer would increase lag and could potentially reduce the magnitude and differences when glucose sensor signals fluctuate between high and low.

    “Simulations of glucose concentration oscillations by Jablecki and Gough concluded that increases in mass transfer would increase lag and could potentially decrease the magnitude and differences when fluctuating between high and low glucose sensor signals.110”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [110] Jablecki M., 2000, Anal. Chem. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Polyurethane allows sufficient oxygen transport while limiting glucose diffusion to the sensor.

    “PU allows for sufficient oxygen transport while limiting glucose diffusion to the sensor.136”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [136] Zhang Y., 1993, Anal. Chim. Acta source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Collagen encapsulation around PU-S-PEO substrates was about 45% thinner than around PU substrates, although capillary density did not differ.

    “The collagen encapsulation surrounding the PU-S-PEO substrates was ~45% thinner than those around the PU substrates though no differences in capillary density were observed.115”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [115] Ward W. K., 2002, Biomaterials source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PLLA foams on non-functioning sensors implanted subcutaneously showed decreased collagen capsule thickness and increased capillary density compared with bare non-functional sensors.

    “When coated onto non-functioning sensors and implanted subcutaneously, the PLLA foams exhibited the expected decrease in collagen capsule thickness and increased capillary density compared to bare non-functional sensors.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [121] Koschwanez H. E., 2008, J. Biomed. Mater. Res. Part A source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In vitro examination of silicone-modified polyurethane significantly inhibited adhesion and FBGC formation, possibly explaining the in vivo benefits observed.

    “In vitro examination of silicone-modified PU was also found to significantly inhibit adhesion and FBGC formation, possibly explaining the in vivo benefits observed.140”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [140] Jones J. A., 2004, J. Biomater. Sci., Polym. Ed. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    After subcutaneous implantation in humans, one of five biosensors functioned for about 6 months, with at least 90% of measured glucose concentrations in the A and B regions of the Clarke Error Grid.

    “Following subcutaneous implantation into humans, one of five biosensors functioned for ~6 months with ≥90% of all measured glucose concentrations falling within the A and B regions of the resulting Clarke Error Grid (i.e., clinically accurate and acceptable, respectively).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [85] Gilligan B. C., 2004, Diabetes Technol. Ther. source

      Not checked in the free run.

  • May combine two claims. The quote only partly states this claim.

    Premisecitation

    Epoxy-polyurethane membranes allowed fabrication of functional glucose sensors in rats for up to 56 days with good sensitivity.

    “The authors reported that this membrane allowed for the fabrication of functional glucose sensors in rats for up to 56 days with good sensitivity.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [141] Yu B., 2006, Biosens. Bioelectron. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Poly(2-hydroxyethylmethacrylate-co-methacrylic acid) implants with 30-40 μm pores increased vascularization and reduced capsule thickness in rat myocardium over 4 weeks.

    “poly(2-hydroxyethylmethacrylate-co-methacrylic acid) implants with 30–40 μm pores were reported to increase vascularization and reduce capsule thickness when placed into the myocardium of rats over a 4-week period.160”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [160] Madden L. R., 2010, Proc. Natl. Acad. Sci. U.S.A. source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductcitation

    The accuracy of hydrogel-coated biosensors was not examined, so the impact of the hydrogel coating on accuracy remains unclear.

    “Even with these benefits, the accuracy was not examined and it is unclear what impact the hydrogel coating would provide in this respect.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [147] Yu B. Z., 2008, Biosens. Bioelectron. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Tissue around porous PVA materials exhibited increased vascularization and decreased collagen capsule thickness.

    “the tissue around the porous materials exhibited increased vascularization and decreased collagen capsule thickness.107”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [107] Sharkawy A. A., 1997, J. Biomed. Mater. Res. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Vascular density adjacent to porous PVA samples was increased relative to controls, with 60 μm pores showing the greatest vascular density.

    “The observed vascular density adjacent to the porous PVA samples was increased relative to controls, with the 60 μm pores exhibiting the greatest vascular density”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [153] Sharkawy A. A., 1998, J. Biomed. Mater. Res. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Sensors lacking the ePTFE membrane were functional for approximately 94 days, with a best-case recalibration interval of 18 days.

    “sensors lacking the ePTFE membrane (i.e., having only an underlying layer of unspecified composition) were functional for approximately 94 d with a best-case recalibration interval of 18 d.156”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [156] Updike S. J., 2000, Diabetes Care source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Hydrogel-coated biosensors were still functional after 21 days, whereas only 13.5% of controls were still functional.

    “Hydrogel-coated biosensors were still functional after 21 days whereas only 13.5% of the controls were still functional.147”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [147] Yu B. Z., 2008, Biosens. Bioelectron. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Only one of nine sensors functioned for 56 days, and seven of nine lost functionality within 17 days or less.

    “However, only one of the nine sensors functioned this long. Indeed, seven of the nine sensors lost functionality in 17 d or less.141”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [141] Yu B., 2006, Biosens. Bioelectron. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Chemical modifications may improve tissue biocompatibility, but they have not led to major improvements in sensor performance in vivo.

    “These results suggest that chemical modifications may improve tissue biocompatibility, but ultimately they have not led to major improvements on sensor performance in vivo.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Porous materials showed a statistically significant increase in total macrophage biomarkers but a significant reduction in pro-inflammatory macrophage biomarkers.

    “porous materials demonstrated a statistically significant increase in total macrophage biomarkers, yet a significant reduction (P < 0.05) in macrophage biomarkers associated with the pro-inflammatory macrophage phenotype.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Control sensor membranes at 28 days had a fibrous capsule of about 500 μm, while capsules around hydrogel-based sensors were roughly 30-60 μm.

    “Control sensor membranes (epoxy-polyurethane) at 28 days were characterized with a fibrous capsule of ~500 Vm while the capsules around hydrogel-based sensors were roughly 30–60 Vm.15”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [15] Wang C., 2008, Biomacromolecules source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Biosensors with an ePTFE membrane having 1-10 μm pores implanted in non-diabetic canines were operable for more than 160 days, with a best-case recalibration interval of 20 days.

    “Updike and coworkers implanted biosensors with an affixed expanded PTFE (ePTFE) membrane having 1–10 μm pores in non-diabetic canines and found they were operable for greater than 160 d with a best-case recalibration interval of 20 d.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [156] Updike S. J., 2000, Diabetes Care source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Tissue surrounding materials with larger or smaller pores was avascular and had thicker, denser collagen capsules.

    “Conversely, tissue surrounding materials with either larger or smaller pores were avascular with thicker, denser collagen capsules.157”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [157] Marshall A. J., 2004, ACS Polym. Prepr.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Pellethane control substrates showed significant inflammatory cell adherence and collagen encapsulation, whereas PEG-modified hydrogels had fewer cells, indicating improved biocompatibility.

    “While Pellethane (i.e., polyurethane) control substrates exhibited significant inflammatory cell adherence and collagen encapsulation, PEG-modified hydrogels were characterized by less cells indicating improved biocompatibility.144”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [144] Quinn C. A. P., 1997, Biomaterials source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Norton et al. observed the expected increase in vascularization due to VEGF but no decrease in local inflammation from dexamethasone release.

    “Norton et al. carefully examined the tissue response to VEGF-, DX-, and VEGF/DX-releasing hydrogels in a rat subcutaneous model,191 observing the expected increase in vascularization due to VEGF but no decrease in local inflammation from DX release.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [191] Norton L. W., 2007, J. Biomed. Mater. Res. Part A source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Overall, the reviewed studies suggest that decreased inflammation likely enhances long-term glucose biosensor functionality, though achieving long-term dexamethasone release while avoiding systemic effects remains challenging.

    “Overall, these studies suggest that decreased inflammation likely enhances long-term glucose biosensor functionality, though the challenges of achieving long-term DX release while avoiding systemic effects remains.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Initial experiments with simultaneous delivery of VEGF and dexamethasone from PLGA particles showed enhanced tissue integration, decreased inflammation, and increased vascularization in a rat model.

    “initial experiments examining the simultaneous delivery of VEGF and DX from PLGA particles showed enhanced tissue integration, decreased inflammation, and increased vascularization in a rat model.189”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [189] Patil S. D., 2007, J. Controlled Release source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Dexamethasone-releasing glucose biosensors retained more than 50% of their original sensitivity 2 weeks after implantation, while control membranes dropped to 15-42% of original levels.

    “DX-releasing glucose biosensors retained >50% of their original sensitivity 2 weeks after implantation, the sensitivity of control membranes dropped to 15–42% of their original levels.187”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [187] Ju Y. M., 2010, J. Biomed. Mater. Res. Part A source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Combined dexamethasone and VEGF release produced a 50% reduction in inflammation after the first week, similar to dexamethasone alone, though inflammation at weeks 2-4 was still greater than with dexamethasone alone.

    “Histology surrounding PLGA particle-containing hydrogels with combined DX and VEGF release revealed a 50% reduction in inflammation after the first week, similar to that of DX release alone, though inflammation at weeks 2–4 was still greater than DX alone.189”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [189] Patil S. D., 2007, J. Controlled Release source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Modulus-matching strategies may help reduce chronic inflammation from motion-damaged tissue, though more empirical evidence is needed.

    “Although more empirical evidence is needed, this strategy may prove helpful in reducing chronic inflammation from motion-damaged tissue.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Dexamethasone-releasing composites still exhibited reduced inflammation and fibrosis compared to control hydrogels at about 3 weeks, demonstrating that local dexamethasone release can arrest fibrous encapsulation.

    “As chronic inflammation set in at ~3 weeks, the DX-releasing composites still exhibited reduced inflammation and fibrosis compared to control hydrogels, demonstrating the ability of local DX release to arrest fibrous encapsulation.188”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [188] Patil S. D., 2004, Diabetes Technol. Ther. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    VEGF is a cytokine released by macrophages and keratinocytes during wound reconstruction to promote angiogenesis.

    “Vascular endothelial growth factor, or VEGF, is a cytokine released by macrophages and keratinocytes during wound reconstruction to promote angiogenesis.195–197”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [195] Werner S., 2003, Physiol. Rev. source

      Not checked in the free run.

    • cites [196] Brown L. F., 1992, J. Exp. Med. source

      Not checked in the free run.

    • cites [197] Frank S., 1995, J. Biol. Chem. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S1 (asserted).

    Premisereasoning

    Local delivery of dexamethasone from glucose biosensors was hypothesized to circumvent undesirable systemic side effects.

    “Local delivery of DX from glucose biosensors was hypothesized to circumvent undesirable systemic side effects of DX.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The functional lifetime of glucose sensors near a VEGF-releasing pump was 63 days, whereas control saline sensors stopped working accurately at 34 days.

    “The functional lifetime of the sensors near the pump was 63 days whereas control (saline) sensors stopped working accurately at 34 days.203”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [203] Ward W. K., 2004, Diabetes Technol. Ther.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Short dexamethasone delivery diminished acute inflammation at 3 and 8 days but inflammation significantly increased at 30 days, indicating that dexamethasone release delayed the immune response.

    “The acute inflammatory response was diminished at 3 and 8 d, but inflammation was significantly increased at 30 d compared to the shorter time points (i.e., 3 and 8 d), indicating that DX release simply delayed the immune response.186”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [186] Bhardwaj U., 2007, J. Diabetes Sci. Technol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    High dexamethasone concentrations over 28 days (0.17 mg/kg) led to a systemic reduction in cortisol levels, while low concentrations (<0.10 mg/kg) did not.

    “high concentrations of DX over 28 d (i.e., 0.17 mg/kg) led to a systemic reduction in cortisol levels while low concentrations (i.e., <0.10 mg/kg) did not cause such effects.181”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [181] Ward W. K., 2010, J. Biomed. Mater. Res. Part A source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Nitric oxide is an endogenously produced free radical synthesized from L-arginine by one of three nitric oxide synthase isoforms: neuronal, endothelial, and inducible NOS.

    “Nitric oxide is an endogenously produced free radical synthesized from L-arginine by one of three isoforms of nitric oxide synthase (NOS): neuronal NOS (nNOS), endothelial NOS (eNOS), and inducible NOS (iNOS).211”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [211] Walford G., 2003, J. Thromb. Haemost. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Differences in outcomes among dexamethasone studies may be due to differences in polymer composition, dexamethasone release kinetics, and/or total dexamethasone payload.

    “The difference in the outcome of these studies may be the result of differences in polymer composition, DX release kinetics, and or total DX payload, clearly indicating the importance of many biomaterial parameters on tissue biocompatibility.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Within 24 h, biosensors in control mice had large reductions in sensitivity, while mice receiving daily dexamethasone injection at the sensor site sustained sensitivity and functionality through 2 weeks regardless of dexamethasone concentration.

    “Within 24 h biosensors in control mice suffered large reductions in sensitivity while mice receiving the daily DX injection at the sensor site experienced sustained sensitivity and functionality through 2 weeks, regardless of DX concentration.192”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [192] Klueh U., 2007, J. Diabetes Sci. Technol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Computational modeling showed that a polyimide material reduced applied strain to surrounding tissue by 94%, while a theoretical 6 MPa material reduced strain by two orders of magnitude.

    “the polyimide material demonstrated a 94% reduction in applied strain to the surrounding tissue, while strain with the theoretical 6 MPa material was reduced by two orders of magnitude.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [169] Subbaroyan J., 2005, J. Neural Eng. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PLGA particles are simple to synthesize, enable slow dexamethasone release, and biodegrade over 2-3 months.

    “These particles are simple to synthesize, enable slow DX release, and biodegrade over 2–3 months.183”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [183] Burgess D., 1994

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S1 (asserted). May combine two claims.

    Premisereasoning

    The combined use of dexamethasone and VEGF was hypothesized to decrease inflammation and enhance vascularization.

    “The combined use of these factors was thus hypothesized to decrease inflammation and enhance vascularization.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Dexamethasone is a glucocorticoid that reduces inflammation.

    “Dexamethasone (DX) is a glucocorticoid that reduces inflammation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Research on nitric oxide storage and release, and on combining nitric oxide release with enzymatic glucose sensing, is still at an early stage.

    “research to date is still in early stages with respect to NO storage and release, and combining the chemistry of NO release with enzymatic glucose sensing.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    New strategies that direct rather than avoid the foreign body response by actively releasing drugs and/or the body's own wound-healing signaling mediators have opened a unique path to alter the natural host response.

    “New strategies for directing rather than avoiding the FBR by the active release of drugs and/or the body’s own signaling mediators of wound healing have created a unique path to alter the natural host response.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Carreau et al. reported reduced leukocyte adhesion at elevated nitric oxide concentrations, suggesting that nitric oxide could reduce localization of inflammatory cells at the device-tissue interface.

    “Carreau et al. reported reduced leukocyte adhesion at elevated NO concentrations, suggesting NO could reduce localization of inflammatory cells at the device-tissue interface.216”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [216] Carreau A., 2011, Exp. Cell Res. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The anti-inflammatory effect correlated with nitric oxide release duration, indicating that benefits may only persist while the interface is releasing nitric oxide, in contrast to Hetrick et al. where long-term reduction in inflammation was observed after cessation of release.

    “The anti-inflammation correlated with the NO-release duration indicating that the observed benefits may only persist as long as the interface is releasing NO, in contrast to observations by Hetrick et al. where long-term reduction in inflammation were observed after cessation of NO release.103,238”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [103] Gifford R., 2005, J. Biomed. Mater. Res. Part A source

      Not checked in the free run.

    • cites [238] Hetrick E. M., 2007, Biomaterials source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In Nichols et al.'s study, collagen encapsulation decreased at 3 and 6 weeks, with the largest effect seen for the highest payloads and longest release.

    “Collagen encapsulation was reduced at 3 and 6 weeks, and the greatest effect was observed for the largest payloads and longest release.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [240] Nichols S. P., 2012, Biomaterials source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Multiple reports indicate that nitric oxide serves as an angiogenic signaling molecule, up-regulating VEGF production and increasing blood vessel growth.

    “Multiple reports indicate that NO serves as an angiogenic signaling model, up-regulating VEGF production and increasing blood vessel growth.213–214”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [213] Cooke J. P., 2003, Atheroscler. Suppl. source

      Not checked in the free run.

    • cites [214] Dulak J., 2003, Antioxid. Redox Signal. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Hetrick et al. found that nitric oxide reduced collagen encapsulation by about 20-25% versus controls at 3 and 6 weeks, mitigated inflammation, and appeared to enhance vascular density at 1 and 3 weeks.

    “In addition to reduced collagen encapsulation (~20–25% vs. controls) observed at 3 and 6 weeks, the NO mitigated inflammation (determined by reduced inflammatory cells near the implant) and appeared to enhance vascular density at 1 and 3 weeks.238”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [238] Hetrick E. M., 2007, Biomaterials source

      Not checked in the free run.

102 of 102

  • The paper relies on this without support.

    Traditional finger-prick glucose monitoring yields only instantaneous readings and cannot provide advance warning of hyperglycemic or hypoglycemic events.

    “such monitoring only provides instantaneous blood glucose concentrations that are unable to warn of hyperglycemic or hypoglycemic events in advance.”

  • The paper relies on this without support.

    Finger-prick sample collection is inconvenient and leads to poor patient compliance.

    “Additionally, the sample collection (i.e., finger prick) method is inconvenient resulting in poor patient compliance.”

  • The authors state this as an assumption.

    CGM systems estimate blood glucose by assuming interstitial fluid glucose is similar enough to blood glucose.

    “CGM systems inherently estimate the blood glucose concentration by assuming the concentration of glucose in interstitial fluids will be similar enough.”

  • The paper relies on this without support.

    The foreign body response is a major hurdle for continuous glucose monitoring performance.

    “address the major hurdles related to the FBR.”

  • The paper relies on this without support.

    The outer sensor membrane protects the enzyme.

    “the outer sensor membrane that serves to protect the enzyme, tune response, and ultimately is responsible for the magnitude of the FBR”

  • The paper relies on this without support.

    The outer sensor membrane tunes the sensor response.

    “the outer sensor membrane that serves to protect the enzyme, tune response, and ultimately is responsible for the magnitude of the FBR”

  • The paper relies on this without support.

    The outer sensor membrane determines the magnitude of the foreign body response.

    “the outer sensor membrane that serves to protect the enzyme, tune response, and ultimately is responsible for the magnitude of the FBR”
7 of 7

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Extended-time CGM generally requires 2-3 weeks stabilization period after surgery and are larger than subcutaneous counterparts.

    “The latter, generally requires 2-3 weeks stabilization period after surgery and are larger than the subcutaneous counterparts 88.”

    From Glucose biosensors in clinical practice: principles, limits and perspectives of currently used devices (2022) · cites this paper as [88]

    Section 2.2 says that fully subcutaneous sensors require surgery and a roughly 2–3-week stabilization period afterward. It says those sensors are larger than percutaneous CGM systems, not larger than subcutaneous counterparts; the claim changes the comparator. (LLM, conf=0.89)

    Experimental — accuracy not yet measured

  • BLE allows transferring state information in small blocks of data at regular intervals, with the processor operating in a low power mode.

    “This protocol allows transferring state information in small blocks of data at regular intervals, where the processor operates in a low power mode.107”

    From Wearables in Medicine (2018) · cites this paper as [107]

    The cited paper’s section on continuous glucose monitoring technologies (§2.2) describes glucose sensors, while its discussion of sensor performance (§3.4) addresses calibration and physiological lag. Neither the supplied passages nor searches for BLE, Bluetooth, wireless communication, small data blocks, and low-power processor operation found a passage addressing the claimed protocol behavior. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

  • For materials larger than 100 μm, greater thickness is generally thought to produce proportionally stronger foreign body responses and fibrosis.

    “At the macro level (>100 μm in size), it is generally held that thicker materials produce a proportionally higher magnitude of foreign body responses and fibrosis3, 21.”

    From Size- and shape-dependent foreign body immune response to materials implanted in rodents and non-human primates (2015) · cites this paper as [3]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Conclusion overlooks reported DX-release sensor results

    Minor

    The paper says the effect of DX release on glucose biosensor performance has not been evaluated, yet it earlier reports sensitivity results for DX-releasing glucose biosensors against controls.

1 of 1

Cites

Flagged first, then by citations

2 of the 246 references couldn’t be matched to a known paper.

Research works printed but not linked: 14

  1. 2012, World Health Statistics 2012
  2. Wang J., 2008, Chem. Rev., 108, 814, 10.1021/cr068123a · DOI · Paper page
  3. Arnold M. A., 2010, In Vivo Glucose Sensing
  4. Vashist S. K., 2012, Anal. Chim. Acta, 750, 16, 10.1016/j.aca.2012.03.043 · DOI · Paper page
  5. 2012, Continuous Glucose Monitoring (CGM) Systems - Global Pipeline Analysis, Competitive Landscape and Market Forecasts to 2017
  6. Henning T., 2010, In Vivo Glucose Sensing
  7. Myrer J. W., 1997, J. Athletic Training, 32, 238
  8. Wilson G. S., 2009, In Vivo Glucose Sensing
  9. Thomé-Duret V., 1996, Diabetes Metab., 22, 174
  10. Helton K. L., 2011, J. Diabetes Sci. Technol., 5, 647, 10.1177/193229681100500318 · DOI · Paper page
  11. Sharkawy A. A., 1998, J. Biomed. Mater. Res., 40, 598, 10.1002/(sici)1097-4636(19980615)40:4 · DOI
  12. Marshall A. J., 2004, ACS Polym. Prepr., 45, 100
  13. Ratner B. D., 2009, ACS Polym. Prepr., 50, 286
  14. Ward W. K., 2004, Diabetes Technol. Ther., 19, 155

Cited by

Sorted by citations

Related

Authors
Nichols, S. P., Koh, A., Storm, W. L., Shin, J. H., & Schoenfisch, M. H.
Affiliations
  • University of North Carolina at Chapel Hill (US)
  • Kwangwoon University (KR)
Corresponding author
Schoenfisch, Mark H.
ORCID
Venue
Chemical Reviews
Publisher
American Chemical Society (ACS)
Published
2013-02-07
Volume
113
Issue
4
Pages
2528-2549
ISSN
  • 0009-2665 (ISSN-L)
  • 1520-6890
DOI
10.1021/cr300387j
PMC
PMC3624030
OpenAlex
W1993893772
Semantic Scholar
15d86c3915bf4d8443f91beee6a62f80dcdc9ac4
Cited by
347
References
246
Citations by year
2026: 20 · 2025: 25 · 2024: 26 · 2023: 26 · 2022: 28 · 2021: 31 · 2020: 23 · 2019: 23 · 2018: 31 · 2017: 20 · 2016: 37 · 2015: 21 · 2014: 20 · 2013: 14
FWCI
2.55
Type
journal article
Language
en
Open access
Locations
  • Chemical Reviews (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institute of Biomedical Imaging and Bioengineering (EB 000708, R01EB000708)
Topics
  • Physical Sciences › Materials Science › Surfaces, Coatings and Films › Polymer Surface Interaction Studies
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
  • Physical Sciences › Engineering › Electrical and Electronic Engineering › Electrochemical sensors and biosensors
Keywords
biomaterials, continuous glucose monitoring, biomedical implants, diabetes mellitus, biocompatibility, glucose sensor, tissue response to implants, inflammation, diabetes complications, diabetes management, diabetes prevention
MeSH terms
Animals, Biocompatible Materials, Blood Glucose, Diabetes Mellitus, Disease Models, Animal, Humans, Polymers, Blood Glucose Self-Monitoring, Biosensing Techniques, Porosity, Elastic Modulus, Electrochemical Techniques

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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