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