Non-Invasive, Continuous,Wearable Blood Glucose Monitor

1.Background

Clinical problem. Clinical need. Current treatments.

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30.3 millionAmericans have diabetes

7thleading cause of death in the United States in 2015

1.25 million have type I diabetes.

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Diabetes: Type I vs. Type IIT1D:

‐ Autoimmune disease causing death of insulin-producing beta cells

‐ Requires insulin therapyT2D:

‐ Insulin resistance- body can make insulin, but not enough

‐ Management with medications and may use insulin

‐ Long-term complications such as heart, nerve and kidney disease

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Left unmonitored/untreated, both types risk additional severe long-term consequences, including blindness, ketoacidosis, stroke, and limb amputation!

Current Solutions‐ Implantable monitoring devices‐ Some non-invasive devices

exist, but have issues: awkwardness, limited accuracy

Current Solutions/monitoring approachesCommon Monitoring Approaches‐ Invasive monitoring techniques ‐ Requiring patients to collect their

blood by pricking their fingers‐ Single-use test strips

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Invasive Continuous MonitoringAdvantages:

‐ Avoid insulin overdose and hypoglycemia

‐ Valuable for monitoring overnight without requiring user interaction

Disadvantages:

‐ Potential surgical procedures‐ Implantation of device in patient ‐ Biocompatibility requirements

Treatments in development Non-invasive Monitors

(Non-continuous) Advantages:

‐ Avoid surgical procedures ‐ Less risk of potential negative

long-term effects from device implantation

Disadvantages:

‐ Not continuous monitoring‐ Requires multiple glucose level

checks daily ‐ Potentially less accurate

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Current Sensors:‐ Optical sensors in Apple watch

measure heart rate using green LED and infrared

‐ ECG measurement by closing a electrical circuit

‐ Apple watch haptics: MEMs actuators (either linear resonant actuator or piezoelectric actuator)

‐ Microphones‐ Pressure sensors‐ Accelerometers

BioMEMS in smart watches

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Desired Sensor Requirements❏ As minimally invasive as possible❏ Continuously monitoring❏ Transmits data to smart device for data integration

and analysis❏ Potentially combine device with smart watch

❏ Alerts user to out of range values ❏ Ability to monitor trends

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2.Semi-invasive glucose sensor

Sensor components. Principles of operation. Fabrication. Advantages & Disadvantages

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Proposed SolutionTwo components: implanted piece (ear or wrist/arm) and external receiver in smart watch

‐ Implanted component senses interstitial glucose, generates signal to transmit information to smart device to be integrated, analyzed and recorded

‐ External receiver: after recording, smart device determines whether action needs to be taken (i.e. insulin delivery or glucose consumption) and alerts user

‐ Bluetooth or wifi communication‐ Calibrate sensor with regular glucometer

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Chemical GLucose Sensor structure

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(Working electrode = Pt electrode)

(Pt electrode)

Molecular–recognition element (GOD enzyme) + signal transducer (electrode)

Limits diffusion of unwanted analytes

Examples: cellulose acetate, poly(vinylpyridine)

Glucose sensor principles

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GOD catalyzes the oxidation of β-D-glucose to produce gluconic acid

Oxygen is reduced to generate hydrogen peroxide (H2O2)

H2O2 in contact with electrode is converted to hydrogen, oxygen, and two electrons

Reaction Scheme:

Measurable current*Indirect glucose detection*

“● Electrode output: current● Second component of device= transducer:

○ Amperometry with Ag/AgCl reference electrode

○ Calibration curve compares current to glucose concentration

● Limitation: H2O2 high positive overpotential → ascorbic acid and acetaminophen may interfere with detection○ Solution: ensure membrane component

is not permeable to these species via size or charge-based selectivity

Transducing Glucose Concentration

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Fabrication● Proposed improvement to current sensors: 3D bioprint a

structure that traps layers of glucose oxidase by exploiting degradable polymers, similar to design of Polypills

● Semipermeable membrane: solvent casting & particulate leaching, electropolymerization

● Platinum microelectrode: wet etching technique

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Advantages & DisadvantagesGlucose oxidase (GOD) has a very high specificity for glucose.

The requirements for industrial production of GOD are minimal and the various components are low-cost.

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Direct interaction between sensor and interstitial fluid enables relatively fast, robust measurements.

Current sensors last a maximum of 14 days→ proposed solution would extend this.

Must be placed under skin (not completely non-invasive).

GOD is used up with reaction.

3.Noninvasive glucose sensor

Sensor components. Principles of operation. Fabrication. Advantages & Disadvantages

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Noninvasive Glucose Monitoring SensorsNear-Infrared (NIR) Spectroscopy

The NIR spectrum operates at a wavelength ranging from 750–2500 nm. The molecular formula for glucose molecule is C6H12O6, which consists of C-H, O-H and C=O bonds.The presence of these bonds causes the absorption of NIR light in blood.

Glucose showed one of the weakest absorption rates

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Calibration and Usage Procedure

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The calibration process was

performed 24 hours before the actual

testing of the system

Run the tests:Invasive and non-invasive

The test results are

displayed in as little as 4

seconds.

NIR Sensor

The total cost of the components of the new device is relatively inexpensive, less than $300, compared to the cost of the current commercially available system.

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PCB FabricationStep 1:

Form design & Output it on the

film

Step 2:Print the Inner

layers & Remove the Unwanted

Copper

Step 3:Layer Alignment & Optical Inspection

Step 4: Layer-up and Bond & Drill

& Plating and Copper Deposition

Step 6: Final Etching

& Solder Mask Application & Surface Finish

Step 5: Outer Layer Imaging &

Plating

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Comparing invasive and NIR Measurements

The results have been compared on determining and benchmarking the glucose levels of five volunteers. This type of glucose meter allows accurate, convenient testing and requires a tiny sample size of only 0.5 microliter.

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Advantages & Disadvantages● Low manufacturing and

maintenance cost

● Non-invasive continuous monitoring

● Shows a very promising future for the implementation of NIR technology in biomedical field especially in optical spectroscopy for real-time and continuous non-invasive glucose monitoring

● Patient variation: skin roughness which can cause light scattering, different body fluids concentration, etc., which could have an impact on the system performance

● Accuracy and robustness of device

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“

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ISO 10993 Testing

Surface components (long-term, skin contact): cytotoxicity, sensitization,

irritation

Implanted components (long-term, blood contact):

add tests for system toxicity, genotoxicity,

implantation, hemocompatibility, chronic

toxicity, and carcinogenicity

Is it a medical device? Yes!

It fits the ISO definition of a medical device because it is a device intended for monitoring of a disease

Foreign Body Response and Biofouling

● Host protein adsorption to device

● Neutrophil infiltration → inflammation

● Fibrous encapsulation by foreign body giant cells, which can interfere with device function (biofouling)

● Concern for implanted component → use non-fouling coating such as PEG?

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02 03

Biocompatibility

Further Testing and Additional Applications Device testing:

○ Generate “Glucose Precision Profile” by testing sensor output compared to known glucose input to ensure accuracy over a wide range of glucose levels

○ For optical sensor: clinical testing would need to include patients with a variety of skin colors, textures, and thicknesses to determine whether certain patient groups may not be able to use this device

● Combine non-invasive glucose monitoring with insulin delivery for closed loop system (“Artificial Pancreas”)

● Optical system could be configured to measure other things by configuring with their absorption spectra

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References1. Ahmad, Majeed. “New AI Features Extend Performance of MEMS Sensors for Wearable Designs.” Electronic Products, 19

Dec. 2018, www.electronicproducts.com/Wearables/New_AI_features_extend_performance_of_MEMS_sensors_for_wearable_designs.aspx.

2. “Diabetic Testing Supplies.” Diabetic Testing Supplies, www.ocresearch.com/pages/diabetic-testing-supplies.html.3. “Glucometer.” Indiamart.com, www.indiamart.com/proddetail/glucometer-14198212373.html.4. Haring, Alexander P., et al. “Programming of Multicomponent Temporal Release Profiles in 3D Printed Polypills via

Core–Shell, Multilayer, and Gradient Concentration Profiles.” Advanced Healthcare Materials, John Wiley & Sons, Ltd, 10 June 2018, onlinelibrary.wiley.com/doi/pdf/10.1002/adhm.201800213.

5. Lanning. “How the Glucose Sensor Works - Ppt Video Online Download.” SlidePlayer, 20 Oct. 2017, slideplayer.com/slide/4214795/.

6. “Manufacturing of Pt-Electrode by Wet Etching.” Microelectronic Engineering, Elsevier, 15 Aug. 2005, www.sciencedirect.com/science/article/pii/S0167931705003552.

7. “MINIMED™ 670G SYSTEMET VÄRLDENS FÖRSTA SJÄLVJUSTERANDE INSULINPUMPSSYSTEM1,2,3.” MiniMed™ 670G-Systemet. Världens Första Självjusterande Insulinpumpssystem, mmc.medtronic-diabetes.se/minimed670g/.

8. Optical Based Noninvasive Glucose Monitoring Sensor Prototype - IEEE Journals & Magazine, ieeexplore.ieee.org/document/7782291.

9. “Pancreatic Islet Transplantation.” National Institute of Diabetes and Digestive and Kidney Diseases, U.S. Department of Health and Human Services, 1 Oct. 2018, www.niddk.nih.gov/health-information/diabetes/overview/insulin-medicines-treatments/pancreatic-islet-transplantation.

10. Radomski, Dariusz, and Jagoda Głowacka. “Sensitivity Analysis of the Insulin-Glucose Mathematical Model.” SpringerLink, Springer, Cham, 18 June 2018, link.springer.com/chapter/10.1007/978-3-319-91211-0_40.

11. Harper, A. and Anderson, M.R. “Electrochemical Glucose Sensors—Developments Using Electrostatic Assembly and Carbon Nanotubes for Biosensor Construction.” Sensors 2010, 10, 8248-8274.

12. Rodbard, David. “Characterizing accuracy and precision of glucose sensors and meters.” Journal of diabetes science and technology vol. 8,5 (2014): 980-5. doi:10.1177/1932296814541810

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Thank You!Questions?