Soft Electronics in Medicine

Nanomaterials-based

Soft Electronics in Medicine

Seoul National University

Chemical and Biological Engineering

Dae-Hyeong Kim

100 mm

2D Graphene 2D Nanomembranes

0D Nanodots 1D Nanowires

Serpentine Percolated structure

Ultrathin Buckling

Additive transfer Intaglio transfer Langmuir Blodgett Molding/templating

Memory Display

Sensors Actuator

50 nm 50 nm

100 mm 200 mm

10 mm

1 nm

500 nm

100 mm

1 mm

30 μm

2 mm

5 mm 3 mm

Device Integration Deformable Design

Assembly Nanomaterials

Nanomaterials, their Assembly, and Soft Devices

ChemNanoMat AOP (2016)

Prosthetic eye ECoG

Prosthetic skin

ECG recording, pacing, ablation

Wearable energy device

Drug diffusion

Transdermal drug delivery Angioplasty

Drug delivery Vital sign

sensing

Home rehabilitation Data storage

EEG

Invasive: Implantable, Minimally invasive device Noninvasive: Wearable devices

Optogenetics

Heat Electricity

Wireless communication Remote healthcare

“Clinical Translation” of “Soft Bioelectronics”

Advanced Materials 28, 4203 (2016)

2. Surgical Tool for Colon Cancer 1. Cardiac Mesh for HF

3. Electronic Patch for Diabetes

4. Patient-Device Interface

Dead

Cardiomyocyte

Myocardial Infarction

& Arrhythmia

LV-RV

Non-synchronization

Cardiac Diseases (Vascular/MI, Arrhythmia/VT, &

LV-RV non-synchronization/reduced LV function)

① Angioplasty

& Stent

② HR Mapping

& RF Ablation

③ Global CRT

RRAM

BES (deflated state)

Temperature sensor Angioplasty for canine common carotid artery

0.6 mm 5 mm

Sheath

Canine common carotid artery

BES Implantation site 10 mm

Inflation with contrast agents Deflation

Catheter with BES 20 mm

Canine common carotid artery

Deployed BES

Volume-rendered CT image

Retractor

20 mm

ACS Nano 9, 5937 (2015)

Minimally Invasive Surgery

(e.g., Angioplasty using Catheter and Stent)

Epicardial Mapping Electrode Array

Science Translational Medicine 2, 24ra22 (2010)

Minimally Invasive Surgical Tools

Time (s)

0 30 60 90 120

V olta ge ( V )

0.0 0.4 0.8 1.2 1.6

Time (s)

20 40 60 80

R (k)

10 12 14

5mm 5mm 2mm

Contact sensor Contact

sensor

CPDMS 3mm

Au

off off

on cont.

Press. Sens.

off off

Impedance cont. sens.

off off off off off

on on on on on on

deflation inflation 4cm contrast agent injection

off on

off

P (kPa)

1200

0 600 Cross-

section

0.0 0.5 1.0 1.5

0.00 0.25

Z (mm)

Y(mm) k=0 at (Z=0.61; Y=0.13)

Deflated balloon

Proc. Nat. Acad. Sci. USA 109, 19910 (2012)

Current Treatments for HF

 Biventricular pacing rapidly enhances cardiac functions, alleviates symptoms, and improves long- term survival in numerous cases

 Two point electrodes on both ventricles may be too

localized to completely restore the global synchronous contractions (need global resynchronization pacing)

• Electrical stimulation therapy

• Passive ventricular restraint

 A device encircling the heart

 To share myofiber stress as well as reduce the size of cardiac chambers

 But over-compression interferes breathing and may cause arrhythmia (need extreme softness)

Multiple point stimulation

Appropriate pressure

Science Translational Medicine 8, 344ra86 (2016)

0 5 10 15 20 25 0

3,000 6,000 9,000 12,000

LE Ag NW conc. (vol%)

σ(S/cm)

Max Cond. ~ 30,000 S/cm Stretchability ~ > 100%

Commercial 1~100 S/cm

Purkinje

network

Electrophysiological Conduction

Tensile strain (%)

Stress (kPa)

Epicardium Cardiac mesh

20 10

0 5 15

2 0 8 10

4 6

Mechanically-matched Design of the Artificial Epicardium

Stretchable Conductive Cardiac Mesh for Global Resynchronization Therapy for Heart Failure Model

Ag NWs with NOBF₄

Ag

PVP NOBF₄

Ag NWs in DMF

LE Ag NWs in toluene

SBS O N

LE Ag NWs with SBS elastomer

HN ^HAm

N O⁺ B^-F F F F

LE Ag NWs in toluene

50 mg/mL Metal: 100,000 S/cm

Customized Design and Biocompatibility

Science Translational Medicine 8, 344ra86 (2016)

Wrap epicardial mesh

No wrap (control)

1 cm 5 mm

RV

+ -

LV I

S S

L₀ = 60 mm

60 55 50 39 34 30 24 20 3 9 -3 -2 44 Max prin.

strain (%)

(1) No significant pressure on ventricle

(2) Histology 3 weeks after

implantation

Science Translational Medicine 8, 344ra86 (2016)

Resynchronization Therapy in Post-MI

Science Translational Medicine 8, 344ra86 (2016)

Recording, Pacing, and Defibrillation

Pre MeshP Pre MeshP Control Post-MI

60

40

20 80

0

***

QR Sd (ms )

QRSd QRSd

Mesh Pacing

Q R

S

Q R

S

• Recording - Surface ECG - Catheter ECG - Mesh ECG

• Defibrillation

• Pacing

- Wide QRSd in post-MI model

- Epicardial mesh reduces QRSd

Conventional electrode

Epicardial mesh

Surface ECG, lead II 2,000 ms 4,000 ms

a' v

a' v

v v

p p

a' v v p

Reduction of Mechanical Wall Stress

Systole

Diastole

160 200 240

1.0 0.5 1.5 2.0 2.5

Time (ms) RAP MeshP

55 60 65

5.0 4.5 5.5 6.0 6.5

Wall stress (x102 kdyn/cm2 )Wall stress (x102 kdyn/cm2 )

Control

0 1 2

0 100

200 300

0 50 100

Post-MI 6

0 4

2

0 100

200 300

0 50 100

• Longitudinal wall stress was derived from simultaneous recordings of LV pressure and myocardial strains during RA pacing and Mesh pacing

• Reduced host myocardial wall stress by acting as an additioal structural component to the LV

Appropriate pressure

Colonoscopy

Eugene Gastroenterology Terese Winslow U.S. Govt.

Colon cancer

 3 ^rd popular cancer (12.9%) in Korea Diagnosis

 Visual observation

 Surgical resection

Smart Endoscope

Nature Communications 6,10059 (2015)

Endoscope

Multifunct. NPs Cancer cells NIR laser (PTT)

Temp.

sensor Contact

sensor Viability sensor Ablation elect.

Tumor/pH sensor

Red laser (PDT)

Visible light TP bio- electronics

GP/Ag NW/GPIrOxEpoxy

Au NR

MSS FL dye Antibody

PDT dye PNIPAAm

Dox

Transparent bio-electronics

Multifunctional Nanoparticles

- Contact sensor - Tumor sensor - pH sensor

- Ablation electrode - Temperature sensor - Viability sensor

- Active targeting - Fluorescent imaging - Photothermal therapy - Photodynamic therapy - Chemotherapy

- Combined therapy

Integration to Endoscope

Nature Communications 6,10059 (2015)

Radius of curvature (mm) Twisting angle (^o)

2 3 4 5 6 7

-25 ΔR/R0(%)

0 25 50

After bending After twisting 0 15 30 45 60 75

8 90

10⁵ 9 Frequency (Hz)

10² 1

Before sterilization After sterilization

10⁴

10 10³

0 1,000 2,000 3,000

Impedance (Ω)

At 120 ℃, 200 kPa

ΔR/R0 (%)

1

Number of cycles 50

0

-50 10 100 1,000

Bending Twisting 100

0

Radius of curvature (mm)

2 4 6 8

0 2000 4000 6000 8000

ΔR/R0(%)

GP ITO 2 mm Transparent

bio-electronics PI/Au

interconnect

Contact pad

2 mm Water

outlet

Laser

2 mm 2 mm

Sterilization

Transfer to endoscope Peel off

Sterilize

GP-based Transparent System

Nature Communications 6,10059 (2015)

250 μm

Temp.

sensor Contact

sensor Viability

sensor Ablation elect.

Tumor/pH sensor

On Off

Temperature (℃)

Time (s) 25

30 35 40 45

0 1 2 3 4Δ0R/R(%)

160 120 80 40 50 55 5

Time (s) 100 200

ΔZ/Z0(%)

Contact On

Off

300 400

400 500 600

200 0

5 mm

Before After

Tumor

Dermis Blood Muscle 5.5

pH

6.0 6.5 7.0 7.5

8.0 *p < 0.001 N = 8 * *

* 8.5

Frequency (Hz)

Impedance (Ω)

10⁴

Normal tissue Tumor tissue

10⁵ 10⁴

10⁵ 10⁶

10³

10⁶ 10⁷

*p < 0.001 N = 8

1 2 3 4 5 6 7 8 Position 1

3 10 30

Impedance (kΩ)

1 Position

pH

2 3 4 5 6 7 8 8.0

7.0

6.0

5.0

4

3 5 6 7

2 1

Porcine intestine

4 mm 1 2 3 Position4 5

Impedance (kΩ)

30

10

6 7 100

300

MaxMin

4 5

2

1 3

7

6 8

4 5

2

1 3

7

6 8

1 cm

55 50 25 30 35 40 45

Temperature (℃) Top view 3 mm

55℃

Agar

20 20 55

Temperature (℃) 25 30 35 40 45 Side view 3 mm

55 ℃ Agar

50 Air

Top view

2 mm Lesion

Side view

2 mm Top Side Lesion

Laser-guiding Smart Surgical Endoscope with Drug-loaded Functional Nanoparticles

Au nanorod Chlorin e6 Rhodamine B

Poly(N-isopropylacrylamide) Cetuximab Mesoporous silica shell

Doxorubicin PTT

50 μm PTT+chemo PDT

Combined

17

Com- bined

Cell viability (%

) 100

50

0

Ctrl. PDTPTT PTT chemo 50 73

43

99 N = 3

180 nm 300

100 200

Temperature (℃)

Size (nm)

20 30 40 50

Heating Cooling

Time (hr) 35 ℃ 65 ℃

Release (%)

0 10 20

100

50

0

50 ℃

Com- bined

Control PTT PTT+

chemo PDT

1 cm

Control PDT PTT PTT+chemo Combined

1 cm 1 cm 1 cm 1 cm 1 cm

Nature Communications 6,10059 (2015)

Laser guiding Optical

fiber

GP device

1 mm GP device

Metal device Tumor

Tumor

T umor V ol ume (mm

)

1,500

Control

PDT PTT PTT+chemo Combined

0 500 1,000

Time (day)

0 5 10 15

N = 3

2,000

20 nm

Diabetes Mellitus

Diabetes

Chronic state of hyperglycemia due to deficiency of insulin secretion Current diagnosis / therapy procedure

Blood samples for test kits (e.g., Accu-chek) Insulin drug (oral) or shot

Hypoglycemia / Hyperglycemia

Abnormally diminished / Excessive glucose in the blood Hyperglycemic state (Too Much Glucose)

Hypoglycemic state (Need More Glucose)

Homeostasis

Overdose Symptoms

Pain Stress

Painless, Stress-free continuous glucose

monitoring & Feedback drug delivery!

Sweat-based Glucose Sensing

• Glucose in the sweat is

closely correlated with that in the blood

• Important factors that affect the sensing is different

between blood and sweat

• Blood: number of red blood cell, temperature, drug molecules

• Sweat: humidity, pH, temperature, drug molecules

Moyer, I. et al. Diabetes Technol. Ther. 14, 398-402 (2012)

A new integrated system is required for sweat-based glucose sensing.

Skin-based Diabetes Monitoring and Therapy

Nature Nanotechnology 11, 566 (2016)

GP-hybrid

a) functional materials (PEDOT, PB, PANi, Ag/AgCl) b) doped graphene

c) serpentine Au mesh a)

b)

c)

Oxi. Red.

ne^-

ne^-

Therapy

viii) micro-needles with drugs (PVP@PCM)

ix) heater (Au mesh/GP) x) temperature sensor (GP) i)

ii)

Therapy

iii) ~ vii)

viii) ~ x)

Sensing

to wireless unit Sensing

iii) humidity (PEDOT)

iv) glucose (PB) v) pH (PANi) vi) count. elect. (Ag/AgCl) vii) tremor (GP)

Sweat control i) sweat-uptake layer

(Nafion)

ii) water-proof film (silicone)

Sweat control

1 cm

Sensing Therapy

Compress (~20 %)

Stretch (~20 %) 2 mm

vii)

iv) iv)

vi) vi)

v) iii) v)

ix) x)

i) i)

ii) ii)

viii)

i)

1 mm 2 mm

In vivo Diabetes Monitoring Test

Sweat 2 mm

Diabetes patch

Wireless monitoring

1 cm

Portable Electrochemical Analyzer With Bluetooth Diabetes

patch Smart phone control/monitoring

2 cm

10 20

Time (min)

0 5 15

Measured RH (%)100

90 80 70 60 50

Wear

diabetes patch Start

measurement

Concentration (mM)

0 0.1 0.5

0 ΔI/I(%)o40

80 120

0.2 0.3 5

7 6 8 pH level

0.4 0.3

Temperature (°C)

Concentration (mM)

0 0.1 0.4

0 40 80 120

0.2 5

25 15

0.5 ΔI/Io(%)

N = 3

pH variation

Samples

Sweat pH

6.0 5.5 5.0 4.5

4.0 1 2 3 4

Subject 1 Subject 2

Blood glucose (Glucose meter)

Sweat glu. (mM)

0.18 Diabetes patch Glucose assay

Blood glu. (mg dL-1) 160 120

40 0.15

0.12 0.09

Time of day (hr)

14 16 17 18 19

12

11 13 15 20 21 22

Lunch Dinner

0.06

80

Breakfast

8 9 10 Cycle (number)

Sensitivity (a.u.)

2 4 6 8 10

0.5

00 1.0

Glucose pH

75

60

45 Sensitivity (mV pH-1)

Nature Nanotechnology 11, 566 (2016)

In vivo Transdermal Drug Delivery

R.T. T>T_c: transition

PVP/

drug Drug

elution PCM

25 40

Temperature (℃)

30 35

Left on Left/right on

Left on Initial

Left/right on

2 mm

Released drug (%)

Temperature (℃) 0

20 40 60

45 33 36 39 42

PCM T_c

T<T_c T>T_c 100

80

2 mm 250 μm

Micro-needles on heater

1 cm

Diabetic mouse 45

Temperature (℃)

30 35

4 mm

40 25

4 mm

Time after treatment (hr)

0 2 4 6

500 400 300 200 100

N = 6

no patch w/o drug w/ drug

*

* *

*

Blood glu. (mg dL-1)

45 (℃)

25 35 30 40

2 mm

i) ii)

iii) iv)

Turn on i) Turn on i)~ii) Turn on i)~iii) Turn on i)~iv)

Turn on i) Turn on i)~ii) Turn on i)~iii) Turn on i)~iv) Initial state

1 mm Heater

off Heater

on

IR sensor Temp. sensor

Time (min) 0

Temperature (℃)

40

30 35 45

1 2 3 4 5

- Thermo-actuated delivery - Stepwise delivery using an embedded multichannel heater

Nature Nanotechnology 11, 566 (2016)

Nanomaterials-based Soft Electronics

3 . Power Supply/Data Storage

- Power Generation Device - Long-term Power Supply - High Charge Capacity

1 . Hybrid-materials

- “Bottom-up” & “Top-down”

Hybrid Nanomaterials and Integration Processes

6 . Wireless System

- Wireless Power/

Data Transmission - Remote Control

2 . Sensors/Electronics

- Bio-Signal Measurement, In-Vivo - Physiological/Electrophysiological Mapping and Feedback Therapy

5 . Soft Substrates/Drug

- Biocompatible Materials - Good Adhesion to Tissue - Drug Delivery Function

- Minimizing strain during stretch or deformation - Low Temperature Process

4 . Stretchable Interconnect

- Ubiquitous High

Performance Diagnosis and Therapy System

7 . Wearable/Implantable System

Data Storage and User Interface??

“Wearable Flash Memory and QLEDs”

40 mm

CTFM array Voltage amplifier

ECG electrode

Heart rate detection Amplification Data storage

Stretching

10 mm 3 mm

Multiplexed CTFM Array 2 mm

300 μm

Word Line

Bit Line Connections for off-chip control

Wearable ECG Sensor, Amplifier, and Flash Memory

V_SS

V_DD V_OUT V_IN

GND 400 μm

GND V_in V_SS

V_DD

V_OUT QT interval

Lead V5

ECG (mV)

Time T

P Lead V1

R

S P

R

S T

Q

0.5 s 100

50

-50 0

Threshold Voltage (V)

Retention Time (s) 0 200 400 600 800 1000 -4

-2 0 2 4 6 8

10 (P) 40V 0.1s

(P) 20V 0.1s (P) 30V 0.1s

(E) -40V 1s

Threshold Voltage (V)

1E0 1E1 1E2 P/E cycle (#) -2

0 2 4 6

1E3 1E4 (P) 30V 0.1s (E) -40V 0.1

s 1 MHz

20 1.0

0.0 0.2 0.4 0.6 0.8

-20 -10 0 10

Applied Voltage (V)

Normalized Cap. (A.U.)

Si Al₂O₃(T_ox)

Trap Al₂O₃

(B_ox) Au electrode

30 Memory capacitors Au Film LB AuNP

AuNP Trap Type :

Science Advances 2, E1501101 (2016)

Electronic Patch: Sensing, Data Storage, and Transdermal DDS

Nature Nanotechnology 9, 397 (2014)

Epidermal, Water-proof Skin Optoelectronics

Nature Communications 6, 7149 (2015)

QLED Electronic Tattoo

Nature Communications 6, 7149 (2015)

Flat Wrinkled

3 mm 3 mm

Quantum Dot LEDs on Everything

Nature Communications 6, 7149 (2015)

Intaglio vs Structured Stamping

Repeat processes (6)

Pick-up QD layer (1)

Aligned transfer (5)

Transfer onto target surface (4)

Slowly detach (3)

Contact on intaglio trench (2)

QD PDMS

Surface treated substrate

Intaglio trench (5) Repeat

processes

Aligned transfer (4)

Structured PDMS stamp

Surface treated substrate

Contact on QD layer

Quickly pick-up QD layer (2) (1)

Transfer onto target substrate (3)

QD layer

Intaglio Printing Structured Stamping

Nature Communications 6, 7149 (2015)

Comparison between Stamping Methods

Nature Communications 6, 7149 (2015)

i ii

Flat stamp

QD layer

Edge of intaglio trench

Fraction of QD layer Crack initiation

Intaglio Printing

i ii

Edge of structured stamp

QD layer

ODTS treated substrate Crack initiation Crack propagation

Structured Stamping

HD : 1366× 768

→ 230 μm

Full HD : 1920× 1080

→ 150 μm

4K UHD : 3840× 2160

→ 75 μm

8K UHD : 7680× 4320

→ 35 μm

Structured stamping

Intaglio printing 40 inch

Flat panel display

60K UHD : 57600× 32400

→ 5 μm

70 μm

N. A.

25 μm

Intaglio printing

Yield distribution

transferred yield (%) 35 μm 150 μm 75μm

20 40 60 100

0 0.4

0 0.6 0.8 1.0

0.2

80 Square patterns

Structured stamping

35 μm 150 μm 75μm

Line patterns

Transferred area (%)

Structured stamping Intaglio printing

Line width (μm) 20 40 60 80 100 0

100

0 90

Ultrahigh Resolution RGB Patterning

Nature Communications 6, 7149 (2015)

Ultrahigh Resolution RGB Patterning

Nature Communications 6, 7149 (2015) VR

(HMD)

retina resolution in VR needs a display of →

2500 ppi (>1500) LCD Small Aperture

(Brightness ) <1000 ppi

OLED Shadow Mask

(Definition ) <1000 ppi QLED OLED Advantages

High Resolution 2460 ppi

iPhone 6 (326 ppi) Galaxy S6 (577 ppi)

LCD OLED

QLED

520 540

560 580

600630 510

490 470

PWQLED

iii

i ii

ii

iii

100 μm 10 μm 100 μm 10 μm

10 μm

100 μm

i

5 mm

Large Area Quantum Dot Patterning

Nature Communications 6, 7149 (2015)

Nature Communications 6, 7149 (2015)