Grand Challenges for EngineeringGrand Challenges for Engineering

Jackie Y. Ying

I tit t f Bi i i d N t h lInstitute of Bioengineering and NanotechnologyAgency for Science, Technology and Research

SingaporeSingapore

www.ibn.a-star.edu.sg

Grand Challenges for Engineering

• A blue-ribbon committee was appointed by the U.S. National Academy of Engineering to identify the grand challenges forAcademy of Engineering to identify the grand challenges for engineering for the next century www.engineeringchallenges.com

William Perry Alec BroersFarouk El-Baz Wesley HarrisBernadine Healy W. Daniel HillisCalestous Juma Dean Kamen Raymond Kurzweil Robert LangerRaymond Kurzweil Robert LangerJaime Lerner Bindu LohaniJane Lubchenco Mario MolínaL P R b t S lLarry Page Robert SocolowJ. Craig Venter Jackie Y. Ying

Grand Challenges for the 21st Century

• 4 key areas whereby engineers can make a distinct impact– Sustainability, Health, Vulnerability, Joy of Living

• 14 Grand Challenges in EngineeringMake Solar Energy EconomicalProvide Energy from FusionDevelop Carbon Sequestration MethodsManage the Nitrogen CycleProvide Access to Clean WaterRestore and Improve Urban InfrastructureAdvance Health InformaticsEngineering Better MedicinesR E i th B iReverse-Engineer the BrainPrevent Nuclear TerrorSecure CyberspaceE h Vi t l R litEnhance Virtual RealityAdvance Personalized LearningEngineer the Tools of Scientific Discovery

IBN’s Efforts Towards Grand Challenges in Engineering

• Focus at the interface between bioengineering and nanotechnology

• Interdisciplinary research bridging science, engineering and medicine via project-oriented teams

• Strengths in synthetic capability for chemicals, materials and biologics

Unique technology platforms that combine novel catalytic• Unique technology platforms that combine novel catalytic chemistry, biomaterials, nanofabricated devices, microfluidic systems with biological and biomedical engineering

• A highly collaborative environment that promotes the sharing of ideas, expertise, and infrastructural support

A lt th t i ti h d t i• A culture that encourages innovative research and nurturing of young talents

Stimuli-Responsive Drug Delivery Systems

Substrate release

Encapsulated substrate

Encapsulated substrate

pH

Substrate release

Polymer

hydrolysis

Hydrogel particle

temperaturetime

Polymer swellingdegradation

Conventional Release Mechanism• Constant or exponential release over time

Hydrogel particle Polymer swelling

Constant or exponential release over time• Responsive to pH or temperature change

Need for Stimuli-Responsive Drug Deliveryp g y• Insulin delivery to patients with diabetes mellitus

– Insulin release in response to glucose concentrationMimic physiological secretion– Mimic physiological secretion

– Eliminate the need for patient blood sugar monitoring

Glucose-Sensitive Polymers

1. Free glucose diffuses into matrix 3. Crosslinking protein releases polymer chains

2. Free glucose competes with polymeric glucose

4. Matrix degrades allowing substrate release

Tetravalent glucose-binding protein (e.g. Con A)

Polymer containing glucosyl groups (e.g. Dextran)y g g y g p ( g )

Free glucose in blood stream

Tailoring of Insulin Delivery Nanoparticles

Glucose-sensitive polymers as insulin carrierProtect insulin to enable oral or nasal delivery Degrade only at high blood glucose concentrationInsulin released upon polymer degradation

Formulation of polymer as nanoparticles – Reverse Microemulsion Small enough to escape macrophage digestionEnhance systemic absorption/bioavailabilityEnhance systemic absorption/bioavailability

N i i

Aqueous Core

d = 5–200 nm

NonionicSurfactant

Continuous Oil PhasePhase

200 nm

Glucose Sensitivity Control

• Increase glucose concentration each hour• Measure gel dissolution by fluorescence

100%

Ligand• Measure gel dissolution by fluorescence

60%

80%

Gel

Dis

solu

tion

0.00.1

Mannose SubstitutionCon A

0%

20%

40%

Cum

ulat

ive 0.1

0.50.91.0

0 200 400 600 800 1000 1200 1400 1600 1800

Glucose Concentration (mg/dl)

• Glucose sensitivity enhanced via greater binding affinity• Glucose sensitivity enhanced via greater binding affinity→ Mannose substitution in Dextran

Dextran-Insulin Release Kinetics

• Glucose-Dependent Gel Dissolution Rate

• Covalent Conjugation of Insulin to Dextran – Prevents insulin leakage through the pores of the gels– 15x increase in release rate from hypo- to hyperglycemia

120%

80%

100%

120%

n R

elea

se

[glucose] (mg/dl)400

80%

100%

120%

ulin

Rel

ease [glucose] (mg/dl)

40080%

100%

120%

ssol

utio

n

[glucose] (mg/dl)

400

40%

60%

ulat

ive

Insu

lin

10050

40%

60%

lativ

e D

ex-In

su

40%

60%

umul

ativ

e G

el D

is

0%

20%

0 50 100 150 200 250

Time (min)

Cum

u

0%

20%

0 50 100 150 200 250

Cum

ul50, 100

Time (min) Time (min)

0%

20%

0 50 100 150 200 250

Time (min)

C

10050

( )

Dextran 70K Dextran-Insulin

( ) ( )

Reversible Gel Dissolution

• 50–250 mg/dl glucose cycles (30-min ramp interval)→ Rapid response time→ Rapid response time

1.2

0.8

1.0

olut

ion

Mannose-Dextran 70 K

TRITC-Labeled

0.4

0.6

elat

ive

Gel

Dis

s

0 0

0.2

Re

0.00 100 200 300 400 500 600

Time (min)

In Vivo Bioactivity

• STZ-induced diabetic rats allowed to eat ad libitum– Dextran-insulin gels lower glucose in vivo

I d d id l l– Increased dosage provides longer control

600

400

500

(mg/

dl)

200

300

Blo

od G

luco

se

0

100

0 1 2 3 4 5

B

Single DoseTriple Dose

0 1 2 3 4 5Days

Functional Morphology of the Kidney

Gomerulus• Hemofiltration

Proximal TubuleProximal Tubule• Reabsorption of glucose,

amino acids, sodium, bicarbonate etcbicarbonate, etc.

• Secretion of creatinine, uric acid,antibiotics, xenobiotics, etc.

• Immunomodulatory functions• 1,25-dihydroxy vitamin D

production

Biohybrid Renal Replacement Microdevice

“New” Blood

Filtration Reabsorption Urine

Blood

Hemodialysis → Membrane filtration of albumin, urea and creatinine

Nutrients Reabsorption → Confluent renal tubule cell monolayer

Development of membrane materials and selection of ECM coatings ─ Porous, non-fouling membranes with sharp MWCO─ Biocompatible membrane and suitable ECM coating to sustain the

f ti f diff ti t d ith li ith t h l iformation of differentiated epithelia with water channel expression

Hydrodynamic extrusion of membranes and cells as hollow fibers

Polymerization by Phase Inversion

• Polymer dissolution in solvent toUV-curable Fullcure700 UV-curable Fullcure700 y

form a viscous polymer solution• UV polymerization• Immersion in water• Immersion in water• Precipitation of polymer to form

porous networkVoid occupied by

the solventVoid occupied by

the solvent

Polysulfone (PS) /Polyacrylonitrile (PAN)

polymer

Polysulfone (PS) /Polyacrylonitrile (PAN)

polymer• Controlled pore size and porosityControlled pore size and porosity• Fine filtration of solids and liquids • Tunable water permeability, sharp molecular weight cut-off• Resistance to chemical attack, good mechanical properties• Excellent biocompatibility, low cost

Multi-Purpose Membrane Technology

BloodDialysing

Fluid

Water

IBN’s Membrane Technology

WaterPurification Hemodialysis,

Kidney Assist Device

Membrane

Waste WaterTreatment

Sea WaterTreatment

Main-Chain Poly-Carbene Catalysts

N-Heterocyclic Carbenes (NHC) as Ligands for Transition Metals─ Similar to electron-rich organophosphanes excellent σ-donating properties Similar to electron rich organophosphanes, excellent σ donating properties

Heterogenization of NHC Catalysts• Versatile main chain polymers• Versatile main-chain polymers

• High catalyst loading

• High stability

NHN NNNNR1 ClCl+ R1

1g y

• Ease of synthesis

• Recyclable particles

+ *R2 BrBr R1 R2n

NNNN R1 NN NN+ +

Br- Br-

2

R

*

NNNN R1 + R3

Br

Br BrR3 NN R1

N

N

R1

Br

BrBr

+

+

Nano Today (2009)Br Br

NN

R1

3(4,5)

Br

+

x x x x

Synthesis of Poly-Imidazolium Particles

+ *R2 BrBr R1 R2 nNNNN R1 NN NN+ +

Br- Br-

2b, R1 = R2 =

2a, R1 = R2 =3a, R1 =

3b, R1 = 4, R1 = R2 =33, Imidazole =

NN2c, R1 = R2 = 3c, R1 =

R2 =

NN

PhPh(Imc)

Chiral Polymer

3b2a 4 332b

• 2,4,6-tris(bromomethyl)mesitylene linker ─ Important towards forming robust network polymer

Main-Chain Polymers as HeterogeneousOrgano and Organometallic Catalysts

Poly-NHC Poly-

Organo and Organometallic Catalysts

Poly-Imidazolium yCarbene

yOrganometallic 3aB-Pd

N+ Br N

N

NaOtBuN

M XMX

ByIonic Solid

PdPtCuNi

3a N+ Br 3aA

NNaO Bu3aB N

M XMXn

MXn / DMSO, heating

Poly-NHC-Pd Catalyzed Suzuki Coupling Reactions of Various Substrates

CrAg

R1X B(OH)2 R1

+ 1-2 % Pdbase

X = I ≥ 99% yield excellent reusabilityX I ≥ 99% yield, excellent reusabilityX = Br 95–99% yield, excellent reusabilityX = Cl 92–99% yield, excellent reusability

Sustainable Technology with Novel Carbene Catalysts

Efficient Conversion of Biomass to 5-Hydroxymethylfurfural

> 80%> 95%Glucose

Fructose

NHC-MCatalyst

1 μm

HMFAngew. Chem. (2008)

• Novel NHC-M catalysts demonstrate highest HMF yields to date

Zhao, et al., Science 2007, 316, 1597CrClx Zhao, et al., Science 2007, 316, 1597 Metal chloride/ionic liquid system HMF yield: 83% for fructose and 68% for glucose

N N RR

• Pure products achieved at low temperatures (80–100°C)

Carbene-Catalyzed CO2 Fixation and Conversion

Carbon Dioxide Fixation by NHCO O

N NR R O C ON NR R

O O

Chem. Commun. 2004, 1, 112

NHC

Direct Conversion of Carbon Dioxide to Methanol

CO2 R3SiOCH3NHC3R3SiH R3SiOSiR3

H2O

R SiOH CH OHRiduan, Zhang and Ying, Angew Chem (2009)R3SiOH CH3OH

• Highly effective organo catalysis • Ambient conditions > 90% yield

Angew. Chem. (2009)

• Ambient conditions, > 90% yield• Oxygen-tolerant, metal-free catalyst

Applications of Nanostructured Materials/Devices

Drug and Protein D li

ChiralPharmaceuticalsDelivery Pharmaceuticals

Synthesis

Fi d P tTissue Engineeringand Implants

Fine and Petro-ChemicalsProcessing

The NanoTool Box

Bioimaging andBi i

Energy and E i t

Medical and Bi l i l D iBiosensing Environment

• Nanotechnology has been successfully developed as a

Biological Devices

Nanotechnology has been successfully developed as atool box to engineer complex systems at multiple lengthscales with unique functionalities

IBN’s Youth Research Program (YRP)• Goal ─ Broad outreach to youth and educators to attract and nurture our future

generation for career in scientific and engineering research

• Since October 2003, we have reached out to over 31,000 students and teachersfrom 204 schools/institutions through Open Houses, Seminars, Workshops

• IBN has trained 1,084 full-time research attachment students, incl. 77 scholars

• Nano Bio Kits ─ Educational kits targeted at students between 15 19 years of age• Nano-Bio Kits ─ Educational kits targeted at students between 15–19 years of age• Exhibited at Tokyo Miraikan Museum (2007), New York Museum of Modern Art (2008)

Di l t h i ChiDielectrophoresis Chip

Thermo-Responsive Hydrogel

Biological Fuel Cell

Engineering Education

• To tackle the grand challenges of the next century, it would be critical to attract the younger generation to the engineering profession

• Need to show the young people how new tool boxes, such as nanotechnology can be created and developed to advance andnanotechnology, can be created and developed to advance and sustain civilization

• To actively foster an interdisciplinary culture to nurture the young t l t th t th k t i t th h h dtalents, so that they can make greater impacts through research and entrepreneurship

• A new direction for Universities whereby School of Engineering works A new direction for Universities whereby School of Engineering works closely with Schools of Science, Medicine, Business and Humanities

– Establish a curriculum that excites and prepares our undergraduateand graduate students to be Renaissance engineersand graduate students to be Renaissance engineers

A New Breed of Engineers

• Communicates effectively with and learn from other disciplines

• Draws new ideas and inspirations from different fields and cultures

• Understands complicated and multifaceted problems that society faces– Forms effective cross-disciplinary team– Ready to adapt and able to think outside the box

K h t d i i ti t l t i f i d t b t l• Knows how to drive innovation, as not only captain of industry, but also leader of new enterprises and policies

• Plays an active role in articulating technological information to the Plays an active role in articulating technological information to the public, and in influencing geopolitical decisions

• Would have a tremendous impact in tackling the grand challenges facing us in sustainability, health, vulnerability, and joy of living

Acknowledgments

Todd ZionEdwin Chow

Jeremy Teo, Daniele ZinkYugen Zhang

Gen Yong, Siti Nurhanna Riduan

Institute of Bioengineering and NanotechnologyAgency for Science, Technology and Researchg y , gy

National Academy of EngineeringSNational Science Foundation