Two-thirds of patients with diabetes avoid regularly monitoring their blood glucose
levels because of the painful and invasive nature of current blood glucose detection.
As an alternative to blood sample collection, exhaled breath condensate (EBC) has
emerged as a promising noninvasive sample from which to monitor glucose levels. However,
this dilute sample matrix requires sensors capable of detecting glucose with high
resolution at nanomolar and micromolar concentrations. Recent developments in EBC
collection methods and highly sensitive glucose biosensors provide a path toward enabling
robust and sensitive glucose detection in EBC. This review addresses current and emerging
EBC collection and glucose sensing modalities capable of quantifying glucose in EBC
samples. We highlight the opportunities and challenges for development and integration
of EBC glucose detection systems that will enable clinically robust and accurate EBC
glucose measurements for improved glycemic control.
Abbreviations:
AgNP (Silver nanoparticles), ALF (Alveolar lining fluid), AlGaN (Aluminum gallium nitride), ASL (Airway surface liquid), BADAN (6-Bromoacetyl-2-Dimethylaminonaphthalene), CDC (Centers for Disease Control), CF (Cystic fibrosis), CGM (Continuous glucose monitoring), ConA (Concanavalin A), COPD (Chronic obstructive pulmonary disorder), EBC (Exhaled breath condensate), ELF (Epithilial lining fluid), ESI (Electrospray ionization), FITC (Fluoresceine isothiocyanate), FRET (Förster resonance energy transfer), GaN (Gallium nitride), GBP (Glucose binding protein), GDH (Glucose dehydrogenase), GOx (Glucose oxidase), HEMT (High electron mobility transistor), HPAEC (High performance anion exchange chromatography), ICU (Intensive Care Unit), ISF (Interstitial fluid), ITC (Isothermal titration calorimetry), KD (Dissociation constant), LC (Liquid Chromatography), MS (Mass spectrometry), NBD (Nitrobenzoxadiazole), NICU (Neonatal Intensive Care Unit), OGTT (Oral glucose tolerance test), PAD (Pulsed amperometric detection), PED (Pulsed electrochemical detection), QD (Quantum dots), QqQ (Triple quadrupole), SMBG (Self-monitoring of blood glucose), SPR (Surface plasmon resonance), TNT (Trinitrotoluene), TOF (Time-of-flight), TR (Texas Red), TWIMS (Traveling wave ion mobility spectrometry), UHPLC (Ultra-high performance liquid chromatography), VOC (Volatile organic compounds), ZnO (Zinc Oxide)To read this article in full you will need to make a payment
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References
- Diagnosis and classification of Diabetes Mellitus.Diabetes Care. 2010; 33: S62-S69https://doi.org/10.2337/dc10-S062
USD of H and H Services, ed.National Diabetes Statistics Report: estimates of diabetes and its burden in the United States 2014.
- Educational guidelines for achieving tight control and minimizing complications of type 1 diabetes.Am Fam Phys. 1999; 60 (1997-1998.): 1985-1992
- Glycemic control in the medical intensive care unit.J Diabetes Sci Technol. 2009; 3: 1330-1341
- Lack of compliance with home blood glucose monitoring predicts hospitalization in diabetes.Diabetes Care. 2001; 24: 1502 LP-1503https://doi.org/10.2337/diacare.24.8.1502
- Diagnosis and classification of autoimmune diabetes mellitus.Autoimmun Rev. 2017; 13: 403-407https://doi.org/10.1016/j.autrev.2014.01.020
- Continuous monitoring of glucose for type 1 diabetes: a health technology assessment.Ont Health Technol Assess Ser. 2018; 18: 1-160
- Standards of medical care in diabetes—2010.Diabetes Care. 2010; 33: S11-S61https://doi.org/10.2337/dc10-S011
- Technologies for continuous glucose monitoring: current problems and future promises.J Diabetes Sci Technol. 2010; 4: 1540-1562
- In vitro measurements of physiological glucose concentrations in biological fluids using mid-infrared light.Biomed Opt Express. 2013; 4: 1083-1090https://doi.org/10.1364/BOE.4.001083
- Composition of interstitial fluid.Clin Chem. 1995; 41: 1522-1525
- Steady state levels of glucose in the different layers of the cornea, aqueous humor, blood tears in vivo.Ophthalmology. 1967; 154: 39-50
- Comparison of salivary and serum glucose levels in diabetic patients.J Diabetes Sci Technol. 2015; 9: 91-96https://doi.org/10.1177/1932296814552673
- Hyperglycemia and cystic fibrosis alter respiratory fluid glucose concentrations estimated by breath condensate analysis.J Appl Physiol. 2007; 102: 1969-1975
- Effect of diabetes mellitus type 2 on salivary glucose – a systematic review and meta-analysis of observational studies.PLoS One. 2014; 9e101706https://doi.org/10.1371/journal.pone.0101706
- Optical glucose sensing in biological fluids: an overview.J Biomed Opt. 2000; 5: 5-16https://doi.org/10.1117/1.429962
- Noninvasive monitoring of glucose levels: is exhaled breath the answer?.J Diabetes Sci Technol. 2012; 6: 659-664https://doi.org/10.1177/193229681200600322
- Airway glucose homeostasis: a new target in the prevention and treatment of pulmonary infection.Chest. 2018; 153: 507-514https://doi.org/10.1016/j.chest.2017.05.031
- Exhaled breath condensate: methodological recommendations and unresolved questions.Eur Respir J. 2005; 26: 523 LP-523https://doi.org/10.1183/09031936.05.00029705
- Current development in non-invasive glucose monitoring.Med Eng Phys. 2008; 30: 541-549
- Dilution of respiratory solutes in exhaled condensates.Am J Respir Crit Care Med. 2002; 165: 663-669https://doi.org/10.1164/ajrccm.165.5.2101018
- A simple method for estimating respiratory solute dilution in exhaled breath condensates.Am J Respir Crit Care Med. 2003; 168: 1500-1505https://doi.org/10.1164/rccm.200307-920OC
- Factors influencing breath condensate volume.Pneumologie. 2001; 55: 414-419https://doi.org/10.1055/s-2001-16947
- Glucose transport in the lung and its role in liquid movement.Respir Physiol Neurobiol. 2007; 159: 331-337
- Proteomics of epithelial lining fluid obtained by bronchoscopic microprobe sampling BT – nanoproteomics: methods and protocols.in: Toms SA Weil RJ Humana Press, Totowa, NJ2011: 17-28https://doi.org/10.1007/978-1-61779-319-6_2
- SGLT1 activity in lung alveolar cells of diabetic rats modulates airway surface liquid glucose concentration and bacterial proliferation.Sci Rep. 2016; 6https://doi.org/10.1038/srep21752
Bicer E.M.Compositional characterisation of human respiratory tract lining fluids for the design of disease specific simulants. 2014:428. https://kclpure.kcl.ac.uk/portal/.
- Factors determining the appearance of glucose in upper and lower respiratory tract secretions.Intensive Care Med. 2003; 29: 2204-2210https://doi.org/10.1007/s00134-003-1961-2
- Pulmonary ventilation BT - comprehensive human physiology: from cellular mechanisms to integration.in: Greger R Windhorst U Springer Berlin Heidelberg, Berlin, Heidelberg1996: 2015-2036https://doi.org/10.1007/978-3-642-60946-6_101
- Why do we have to move fluid to be able to breathe?.Front Physiol. 2012; 3: 146
- Exhaled breath condensate – from an analytical point of view.Biochem Med. 2013; 23: 281-295https://doi.org/10.11613/BM.2013.034
- Noninvasive measurement of plasma glucose from exhaled breath in healthy and type 1 diabetic subjects.Am J Physiol - Endocrinol Metab. 2011; 300: E1166-E1175
- Ion mobility and liquid chromatography/mass spectrometry strategies for exhaled breath condensate glucose quantitation in cystic fibrosis studies.Rapid Commun Mass Spectrom. 2013; 27: 2263-2271https://doi.org/10.1002/rcm.6683
- Exhaled breath condensate—an overview.Immunol Allergy Clin North Am. 2007; 27 (587-v)https://doi.org/10.1016/j.iac.2007.09.001
- Comparison of two methods for exhaled breath condensate collection.Allergy. 2006; 61: 1016-1018https://doi.org/10.1111/j.1398-9995.2006.01064.x
- Time lag of glucose from intravascular to interstitial compartment in humans.Diabetes. 2013; 62: 4083-4087
- Assessing dead space. A meaningful variable?.Minerva Anestesiol. 2006; 72: 521-528
- Exhaled breath condensate: technical and diagnostic aspects.Sci World J. 2015; 2015https://doi.org/10.1155/2015/435160
- Selective collection and condensation of exhaled breath for glucose detection..in: 2018 Fourtieth annual international conference of the IEEE engineering in medicine and biology society (EMBC). 2018: 3890-3893https://doi.org/10.1109/EMBC.2018.8513393
Blanch L, Romero PV, Lucangelo U Capnografia volumétrica Min Anest2006. 2006;72:1–9. papers2://publication/uuid/A4BAD9ED-E5E3-49AF-A96F-084A984B9A91.
- CO2-controlled sampling of alveolar gas in mechanically ventilated patients.J Appl Physiol. 2001; 90: 486-492https://doi.org/10.1152/jappl.2001.90.2.486
Mohan AP. Establishing a functional relationship between the glucose concentrations in exhaled breath condensates and blood, [Master's thesis], Purdue University, 2010 (AAI1489569).
- Breath condenser coatings affect measurement of biomarkers in exhaled breath condensate.Eur Respir J. 2006; 28: 1036-1041https://doi.org/10.1183/09031936.06.00110305
- Standardizing the collection and measurement of glucose in exhaled breath and its relationship to blood glucose concentrations.([Master's thesis], Purdue University,)2014 (AAI1572516)
- Glucose concentrations in parotid fluid and venous blood of patients attending a diabetic clinic.J R Soc Med. 1981; 74: 725-728
- Salivary characteristics of diabetic children.Braz Dent J. 2003; 14: 26-31
- Salivary glucose concentration and excretion in normal and diabetic subjects.J Biomed Biotechnol. 2009; 2009430426https://doi.org/10.1155/2009/430426
- Pulmonary perspective collection and analysis of exhaled breath condensate in humans.Am J Respir Crit Care Med. 2001; 164: 731-737https://doi.org/10.1164/ajrccm.164.5.2101032
- Chronic obstructive pulmonary disease and diabetes mellitus: a systematic review of the literature.Respiration. 2015; 89: 253-264https://doi.org/10.1159/000369863
- Role of airway glucose in bacterial infections in patients with chronic obstructive pulmonary disease.J Allergy Clin Immunol. 2018; 142 (e6): 815-823
- Exhaled breath condensate pH standardised for CO2 partial pressure.Eur Respir J. 2007; 29: 496 LP-501https://doi.org/10.1183/09031936.00084006
- Electrochemical glucose biosensors.Chem Rev. 2008; 108: 814-825https://doi.org/10.1021/cr068123a
- Analyzing breath samples of hypoglycemic events in type 1 diabetes patients: towards developing an alternative to diabetes alert dogs.J Breath Res. 2017; 11: 26007
- Glucose biosensors: an overview of use in clinical practice.Sensors. 2010; 10: 4558-4576https://doi.org/10.3390/s100504558
- Introduction to biosensors.Essays Biochem. 2016; 60: 1-8
- Biosensor recognition elements.Curr Issus Mol Biol. 2008; 10: 1-12
- Wearable non-invasive epidermal glucose sensors: a review.Talanta. 2018; 177: 163-170
- Smartphone based non-invasive salivary glucose biosensor.Anal Chim Acta. 2017; 996: 54-63
- The evaluation of a low-cost colorimeter for glucose detection in salivary samples.Sensors. 2017; 17: 2495https://doi.org/10.3390/s17112495
- A glucose oxidase-coupled DNAzyme sensor for glucose detection in tears and saliva.Biosens Bioelectron. 2015; 70: 455-461
- Glucose oxidase — an overview.Biotechnol Adv. 2009; 27: 489-501
- Electrical communication between redox centers of glucose oxidase and electrodes via electrostatically and covalently bound redox polymers.J Am Chem Soc. 1989; 111: 2357-2358https://doi.org/10.1021/ja00188a091
- Direct electrical communication between chemically modified enzymes and metal electrodes. I. Electron transfer from glucose oxidase to metal electrodes via electron relays, bound covalently to the enzyme.J Phys Chem. 1987; 91: 1285-1289https://doi.org/10.1021/j100290a001
- Review of glucose oxidases and glucose dehydrogenases: a bird's eye view of glucose sensing enzymes.J Diabetes Sci Technol. 2011; 5: 1068-1076
- Glucose sensors: a review of current and emerging technology.Diabetes Med. 2009; 26: 197-210https://doi.org/10.1111/j.1464-5491.2008.02642.x
- A high-throughput colorimetric assay for glucose detection based on glucose oxidase-catalyzed enlargement of gold nanoparticles.Nanoscale. 2015; 7: 15584-15588https://doi.org/10.1039/C5NR03758A
- Colorimetric and ratiometric fluorescence dual-mode sensing of glucose based on carbon quantum dots and potential UV/fluorescence of o-diaminobenzene.Sensors. 2019; 19https://doi.org/10.3390/s19030674
- Time-resolved fluorescent detection for glucose using a complex of luminescent layered titanates and enzymes.Anal Sci. 2017; 33: 989-991https://doi.org/10.2116/analsci.33.989
- Electrode systems for continuous monitoring in cardiovascular surgery.Ann N Y Acad Sci. 1962; 102: 29-45https://doi.org/10.1111/j.1749-6632.1962.tb13623.x
- Highly selective membrane-free, mediator-free glucose biosensor.Anal Chem. 1994; 66: 3600-3603https://doi.org/10.1021/ac00093a011
- The glucose binding protein as glucose sensor.in: Geddes CD Lakowicz JR Glucose Sensing. Springer US, Boston, MA2006: 323-331https://doi.org/10.1007/0-387-33015-1_13
- Biocatalytic implant of Pt nanoclusters into glucose oxidase: a method to electrically wire the enzyme and to transform it from an oxidase to a hydrogenase.J Phys Chem Lett. 2010; 1: 2816-2819https://doi.org/10.1021/jz1011324
- Direct electrochemistry of glucose oxidase and biosensing for glucose based on graphene.Anal Chem. 2009; 81: 2378-2382https://doi.org/10.1021/ac802193c
- Direct electrochemical reduction of single-layer graphene oxide and subsequent functionalization with glucose oxidase.J Phys Chem C. 2009; 113: 14071-14075https://doi.org/10.1021/jp906348x
- Recent advances in electrochemical glucose biosensors: a review.RSC Adv. 2013; 3: 4473-4491https://doi.org/10.1039/C2RA22351A
- Electrochemical quartz crystal microbalance studies on enzymatic specific activity and direct electrochemistry of immobilized glucose oxidase in the presence of sodium dodecyl benzene sulfonate and multiwalled carbon nanotubes.Biotechnol Prog. 2008; 24: 262-272https://doi.org/10.1021/bp070256+
- Enzymatic glucose detection using ZnO nanorods on the gate region of AlGaN∕GaN high electron mobility transistors.Appl Phys Lett. 2007; 91252103https://doi.org/10.1063/1.2825574
- Aluminum gallium nitride (GaN)/GaN high electron mobility transistor-based sensors for glucose detection in exhaled breath condensate.J Diabetes Sci Technol. 2010; 4: 171-179https://doi.org/10.1177/193229681000400122
- Stimuli-responsive hydrogel–silver nanoparticles composite for development of localized surface plasmon resonance-based optical biosensor.Anal Chim Acta. 2008; 611: 205-211
- A new nanobiosensor for glucose with high sensitivity and selectivity in serum based on fluorescence resonance energy transfer (FRET) between CdTe quantum dots and Au nanoparticles.Chem – A Eur J. 2008; 14: 3637-3644https://doi.org/10.1002/chem.200701871
- Optical methods for sensing glucose.Chem Soc Rev. 2011; 40: 4805-4839https://doi.org/10.1039/C1CS15063D
- Glutathione-capped CdTe quantum dots for the sensitive detection of glucose.Talanta. 2009; 77: 1858-1863
- Use of CdSe/ZnS core-shell quantum dots as energy transfer donors in sensing glucose.Talanta. 2007; 73: 899-905
- Quantum dot-based FRET for sensitive determination of hydrogen peroxide and glucose using tyramide reaction.Talanta. 2013; 106: 79-84
- A new route to the considerable enhancement of glucose oxidase (GOx) activity: the simple assembly of a complex from CdTe quantum dots and GOx, and its glucose sensing.Chem – A Eur J. 2008; 14: 9633-9640https://doi.org/10.1002/chem.200800681
- An Injectable PEG-BSA-Coumarin-GOx Hydrogel for Fluorescence Turn-on Glucose Detection.Appl Biochem Biotechnol. 2015; 177: 1115-1126https://doi.org/10.1007/s12010-015-1800-2
- Recent Developments in Optical Detection Technologies in Lab-on-a-Chip Devices for Biosensing Applications.Sensors (Basel). 2014; 14: 15458-15479https://doi.org/10.3390/s140815458
- On the mechanism of immobilized glucose oxidase deactivation by hydrogen peroxide.Biotechnol Bioeng. 1982; 24: 2419-2439https://doi.org/10.1002/bit.260241109
- A novel reagentless sensing system for measuring glucose based on the galactose/glucose-binding protein.Anal Biochem. 2001; 294: 19-26
- Fluorescence glucose detection: advances toward the ideal in vivo biosensor.J Fluoresc. 2004; 14: 535-547https://doi.org/10.1023/B:JOFL.0000039341.64999.83
- Near-infrared fluorescence lifetime assay for serum glucose based on allophycocyanin-labeled concanavalin A.Anal Biochem. 2001; 292: 216-221
- A fluorescence lifetime-based fibre-optic glucose sensor using glucose/galactose-binding protein.Analyst. 2011; 136: 968-972https://doi.org/10.1039/C0AN00430H
- Dual-labeled glucose binding protein for ratiometric measurements of glucose.Anal Chem. 2004; 76: 1403-1410https://doi.org/10.1021/ac035063p
- Portable system for the detection of micromolar concentrations of glucose.Meas Sci Technol. 2014; 25: 25701
- Fiber optic biosensor for transdermal glucose based on the glucose binding protein.Sens Actuators B Chem. 2017; 242: 569-576
- Fluorescence-based sensing of glucose using engineered glucose/galactose-binding protein: a comparison of fluorescence resonance energy transfer and environmentally sensitive dye labelling strategies.Biochem Biophys Res Commun. 2008; 365: 102-106https://doi.org/10.1016/j.bbrc.2007.10.129
- Fluorescence resonance energy transfer glucose sensor from site-specific dual labeling of glucose/galactose binding protein using ligand protection.J Diabetes Sci Technol. 2012; 6: 1286-1295https://doi.org/10.1177/193229681200600607
- Self-assembled nanoscale biosensors based on quantum dot FRET donors.Nat Mater. 2003; 2: 630-638
- Spectral characteristics of the mutant form GGBP/H152C of D-glucose/D-galactose-binding protein labeled with fluorescent dye BADAN: influence of external factors.in: Uversky V 2. PeerJ., 2014: e275https://doi.org/10.7717/peerj.275
- A fluorescence resonance energy transfer sensor based on maltose binding protein.Bioconjug Chem. 2003; 14: 909-918https://doi.org/10.1021/bc020062+
- Fluorescence-based glucose sensors.Biosens Bioelectron. 2005; 20: 2555-2565
- Photo-crosslinked copolymers of 2-hydroxyethyl methacrylate, poly(ethylene glycol) tetra-acrylate and ethylene dimethacrylate for improving biocompatibility of biosensors.Biomaterials. 1995; 16: 389-396
- A fluorescence affinity hollow fiber sensor for continuous transdermal glucose monitoring.Anal Chem. 2000; 72: 4185-4192https://doi.org/10.1021/ac000215r
- In vitro long-term performance study of a near-infrared fluorescence affinity sensor for glucose monitoring.Biosens Bioelectron. 2004; 19: 905-914
- Optical assay for glucose based on the luminescnence decay time of the long wavelength dye Cy5TM.Sens Actuators B Chem. 1997; 45: 93-99
- Fluorescence resonance energy transfer from allophycocyanin to malachite green.Chem Phys Lett. 1999; 309: 395-401
- Recent advances in electrochemical non-enzymatic glucose sensors – a review.Anal Chim Acta. 2018; 1033: 1-34
Umr I. Poster session abstracts CTFR models of three-dimensional structure of CTFR in open and closed forms. 2006;4:220–459.
- High-performance anion-exchange chromatography coupled with pulsed electrochemical detection as a powerful tool to evaluate carbohydrates of food interest: principles and applications.Int J Carbohydr Chem. 2012; 2012: 1-13https://doi.org/10.1155/2012/487564
- Detection of carbohydrates using a pre-column derivatization reagent 1-(4-isopropyl) phenyl-3-methyl-5-pyrazolone by high-performance liquid chromatography coupled with electrospray ionization mass spectrometry.J Chromatogr B. 2010; 878: 1135-1144
- The promise and perils of exhaled breath condensates.Am J Physiol Cell Mol Physiol. 2004; 287: L1073-L1080https://doi.org/10.1152/ajplung.00069.2004
- Continuous glucose sensor using novel genetically engineered binding polypeptides towards in vivo applications.Sens Actuators B Chem. 2010; 149: 51-58
- Environmental temperature and relative humidity influence exhaled breath condensate pH.Eur Respir J. 2008; 31: 474-475https://doi.org/10.1183/09031936.00128007
- Hydrogen peroxide in exhaled air: a source of error, a paradox and its resolution.ERJ Open Res. 2016; 2: 00052-02015https://doi.org/10.1183/23120541.00052-2015
- Effects of ventilation on the collection of exhaled breath in humans.J Appl Physiol. 2004; 96: 1371-1379https://doi.org/10.1152/japplphysiol.01034.2003
Article info
Publication history
Published online: May 30, 2019
Accepted:
May 26,
2019
Received in revised form:
May 2,
2019
Received:
March 3,
2019
Footnotes
Jacqueline C. Linnes, Ph.D. is an Assistant Professor in the Weldon School of Biomedical Engineering at Purdue University. Dr. Linnes's research program is focused on developing and translating real-time detection technologies using non-invasive sample collection, microfluidic sample preparation, and automated detection of biomolecules for efficient diagnosis and monitoring of diseases at the point of care.
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