MEMS Sensor Systems and IoT Part I(cavity)Cavitas biosensors using biocompatible

polymer and MEMS techniques

Kohji MitsubayashiInstitute of Biomaterials and Bioengineering TOKYO MEDICAL and DENTAL UNIVERSITY

MEM Engineer Forum 2017April 26 - 27, 2017, KFC Hall Ryogoku, Tokyo, Japan

Outline Concept of “Cavitas sensors” for non-invasive

bio/chemical monitoring as daily medicine.

Soft contact-lens type biosensorusing Soft-MEMS techniques.# Fabrication w/ biocompatible polymers# Evaluation of sensor behavior# Tear sugar monitoring

Mouth guard type biosensor with BLE 4.0 telemetric system

Wearable sensor tech.

Transcutaneous O2 (tcPO2) sensor

Oraganic + MEMS

Sensors and Actuators B 95: 373–377, 2003Sensors and Actuators B 108: 733–737, 2005Biomed Microdevices 9:1–6, 2007

Opt. transparent

[1] Soft-CL Biosensor

Tear sugar analysis

[2] Body Area Network

Biomed Microdevices, 11:837–842, 2009Talanta 83: 960–965, 2011Biomed Microdevices (2011) 13:603–611, 2011Materials Transduction, 53: 1657-1664, 2012Analytical Letters, 47: 1361–1374, 2014

Biosensors and Bioelectronics 22: 558–562, 2006Biomed Microdevices 9:603–609, 2007Anal Bioanal Chem 391:1269–1274, 2008Photopolymer Sci. 23: 167-170, 2010Materials Transactions, 52: 1943-1948, 2011

Anal. Sci. 17: 773-775, 2001Biosensors and Bioelectronics 19: 67/71, 2003

Wearable bio/chemical sensors and Sensor communication system

Self analysis

Portable inst.physical & mental sufferinginfection

component Contained amount (mg/dl)

ascorbic acid 0.14citric acid 0.60urea 0.04ammonium 5.00glucose 2.60 (0.14 mM)amino acid 7.58

Components of tear fluids

Investigation of SCL type biosensor with flexible sensor techniques

Biological Information on Eye Site

diabetic patient6.9 million in Japan

15.7 million in USA

diabetic retinopathydiabetic nephrosclerosis

(intensity)

5 min time-delay

disease complication

Soft Contact lens (CL) glucose sensor

Requirements• Optical transparency • Flexibility & mechanical strength• Utility as a contact lens

1. Sensor fabrication

• Design & fabrication• Electrode deposition• Characterization

2. Material investigation

• Biocompatibility • Polymer synthesis• Enzyme immobilization

H2O2 (enzymatic product)

glucose

GODglucose + O2 gluconic acid + H2O2

Pt

Ag/AgCl

+400 mv vs. Ag/AgCl

(a) PDMS to lower-template

(b) CL with upper-template

(c) Drying

(d) Release from template

Soft-CL electrode construction with polymer and MEMS

sputtering

Mask sputter deposition

Ti stencil

Ti stencil fabricationLaser marking system

poly-dimethyl siloxane

Sputtering method Formed film on PDMS

Ion Beam Sputtering

Parallel Plate Sputtering Cracks and pealing off

Sufficient adhesion!

Sputtering method on PDMS sheet

Soft-CL type electrode

glucose ＋ O2 gluconic acid ＋ H2O2GOD

enzyme reaction

PMEH by radical polymerizationIII. Dialysis IV. Re-precipitation

PMEH

II. Radical polymerization

V. Dryingdialysis tube

reflux condenser

three-neckedflask

oil bath

solvent (80wt%)

polymerization initiator

Ar bubbling（deoxidization）

I. Preparation of monomer

monomer (20wt%) drying tube

Removal of residual monomerby agitation with stirrer collect rate = 27.2 [%]

Enzyme immobilization on soft-CL Biocompatible MPC polymerOrganic synthesis of biocompatible polymer for Soft-CL biosensor

without any anesthetic

Application of SCL sensor on Rabbit eye siteExperimental set-up for continuous monitoring of tear glucose

sex：male

age：7 months

weight：3.6 kgretainer

Japan white rabbit

Output current of CL biosensor

Calibration range

0.03~5.0mmol/l

glucose concentration (mmol/l)

outp

ut c

urre

nt (µ

A)

glucose concentration (mmol/l)

outp

ut c

urre

nt (µ

A)

Continuous monitoring of tear glucose

Ave. : 0.022 µA

estimated tear glu. : 0.13 mmol/l

(reported value 0.14 mmol/l)

Calibration curve for glucose Calibration curve for glucose

Calibration range

0.03~5.0mmol/l

before after

Before application After application

11

Glucose administration

Microscopic examination

Oral glucose tolerance test (OGTT)Comparison between tear and blood

No damage such as irritation

Tear fluid : Future potential as non-invasive sample for diabetes

continuous

before after

glucose administration

8min delay

dosage amount: 1g/weight-kg

Following blood change

blood

needleglucose

Tear glucose Blood glucose

fixator

Mouthguard biosensor for Saliva glucose mentoring

Saliva chemicals

glucoseascorbic acidureauric acidammoniacitric acid

mM

mMmMmMmM

μM

steady irritant

0.055 0.05610.4±4.3 4

3.22 2.170.09 0.18

0.01-0.060.004

(Data Book of Biochemistry 1980, Tokyo Kagaku Dojin) (Journal of the Japan Diabetes Society 1997;40)

Glucose b/w blood & saliva

Saliva monitoring for non‐invasive evaluation

12

Biosensor Mouthguard type biosensor

・enzyme immobilization・bonding to mouthguard・safety

Biocompatible polymer Mouthguard material

Use application・sports・teeth aligner・clenching protection・occlusal harmony

Shape forming sheet

Real time measurement of saliva glucose for non‐invasive blood glucose evaluation

glucose + O2 gluconolactone + H2O2GOD

Enzyme reactionSaliva glucose monitoringby mouthguard biosensor

GOD : glucose oxidase

Conclusions & Acknowledgements

Conclusions1) Soft CL biosensor was fabricated using Soft-MEMS

techniques and biocompatible polymers. # calibration range: 0.03 – 5.0 mmol/l# capable of continuous & real time tear sugar monitoring

2) Mouthguard telemetric biosensor was developed using hard dental material and BLE 4.0 tech.# detail and physiological results, soon.

AcknowledgementsResearch funding supports » JST A-STEP program» MEXT “Next-Generation Actuators

Leading Breakthroughs”» MEXT “Advanced Research Program in

Sensing Biology”.» JSPS Grant-in-Aid for Scientific Research» JSPS Grant-in-Aid for Exploratory» JST Tokyo-CREATE

Thank you !