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NanoNano--Robotics in Medical Applications:Robotics in Medical Applications:From Science Fiction to RealityFrom Science Fiction to Reality

Constantinos Mavroidis, Ph.D., Professor

Bio Nanorobotics Laboratory

Department of Mechanical and Industrial Engineering

Northeastern University, Boston, Massachusetts

http://www.bionano.neu.edu

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Northeastern UniversityNortheastern University

George J. Kostas Nanomanufacturing Center

at Northeastern University

1. Entrepreneur, CorporateOutreach and Staff Area

2. Soft Lithography andWet Chemistry Lab

3. Lithography andCharacterization

4. Cleanroom Facility

Located in Boston MA

Created in 1898 14,000 Undergraduates

3,500 Graduate Students

90 PhD Programs Experiential Learning /

Cooperative Education

Leader inNanomanufacturing

Strong PhD Program inNanomedicine

Facilities at the Kostas NanomanufacturingCenter

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NanomedicineNanomedicine

Healthcare Applications of

Nanomedicine(Wagner et al., Nature Biotechnology, 2006)

Nanomedicine is the process ofdiagnosing, treating, and preventing diseaseand traumatic injury, of relieving pain, and ofpreserving and improving human health, usingmolecular tools and molecular knowledge ofthe human body.(Freitas, 2006)

Nanomedicine: Application ofnanotechnology in medicine.

Nanotechnology refers to the science andengineering activities at the level of atoms andmolecules. A nanometer is a billionth of ameter, that is, about 1/80,000 of the diameterof a human hair, or 10 times the diameter of ahydrogen atom.

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Market and Activity EvolutionMarket and Activity Evolution

Nanomedicine Patents and Publications (Wagner et al., Nature Biotechnology, 2006)

Nanomedicine Market:$6.8B in 2004; $12B in 2012(Wagner et al., Nature Biotechnology, 2006)

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CollaborationCollaborationA truly multidisciplinary fieldA truly multidisciplinary field

Nanomedicine

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Role of Nanotechnology in Medical ResearchRole of Nanotechnology in Medical Research

Basic Research

Molecular Biology

Genetics

Proteomics

Systems Biology

.

Nanotechnology

Nanomanufacturing

Nanoimaging

Nanosensing

Nanomanipulation

Computational Tools

.

Biomedical Devices

Tissue Regeneration

Drug Delivery

In-vitro Diagnostics

Implantable Devices

Smart Nanoparticles

NanoRobotics

.

Translational ResearchCancer

Heart

Brain

.

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The NanoRobotic Concept

Nanorobots would constitute any smart structurecapable ofactuation, sensing, signaling, information

processing, intelligence, manipulation and swarmbehaviorat nano scale (10-9m).

Bio nanorobots Nanorobots designed (and inspired) byharnessing properties of biological materials (peptides,

DNAs), their designs and functionalities. These areinspired not only by nature but machines too.

Nanorobots could propose solutions at most of thenanomedicine problems

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NanoRobotics An Example:Ultra-Local Drug Delivery

Bio-Nano-Robot Repairing a Damaged Blood Cell

(Opensource Handbook of Nanoscience and Nanotechnology)

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Bio Sensors

DNA Joints

HA a-helix

A bio nano robot

Representative Assembly

of bio components

Assembled bio

nanorobots

Bio nano

components

A bio nanocomputational cell

Bio nano swarms

Distributive

intelligence

programming &

control

A Bio nano information

processing component

Conceptual automatic

fabrication floor

Automatic

fabrication and

information

processing

The Roadmap Towards NanoRobotics

STEP 1 STEP 2 STEP 3 STEP 4

Research Progression

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Bottom Up Approach Based on

Macro-Nano EquivalenceStructural Elements

Metal, Plastic Polymer DNA, Nanotubes

Actuators

Electric Motors,

Pneumatic Actuators,

Smart Materials, Batteries,

etc.

ATPase, VPL Motor, DNA, CNT

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Bottom Up Approach Based on

Macro-Nano EquivalenceSensors

Light sensors, force sensors,position sensors, temperature

sensors

Joints

Revolute, Prismatic,

Spherical Joints etc.

DNA

Nanodevices,

Nanojoints

Rhodopsin,

Heat Shock

Factor,

CNT based

Nanosensors

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State of the Art on NanoRobotics:Nanomanipulators

NanoRobotics for Molecular Biology

Cell Manipulation Using Nanomanipulators(e.g. automated DNA injection - Prof. Brad Nelsons group at ETH)

Commercial Nanomanipulators (e.g. Zyvex Corp.)

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State of the Art on NanoRobotics:MRI Guided Nanoparticle

In vivo automatic navigation of a 1.5 mm ferromagnetic bead inside thecarotid artery of a living swine (Martel et al., 2007, Applied Physics Letters).

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State of the Art on NanoRobotics:Smart Nanoparticles

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State of the Art on NanoRobotics:

Protein Based Nano Motors and SensorsProtein Based Molecular MachinesProtein Based Molecular Machines ATPATP SynthaseSynthase Motors,Motors, MyosinsMyosins,, KinesinsKinesins andand DyneinsDyneins, Bacterial Flagella, Bacterial Flagella

MotorsMotors

Advantages: Natural, High Efficiency and PowerAdvantages: Natural, High Efficiency and Power

Disadvantages: Bulky, Hard to Interface, Customize and Design, CDisadvantages: Bulky, Hard to Interface, Customize and Design, Complexomplex

Flagella in Bacterial MembraneATP Synthase ATPase Visualization1

Myosin Kinesin

Dynein MoleculeSteffen et al., Biol. Bulletin. 193, 221-222

1Noji et al., Nature, 386:(6622), 299-302

1 m diameter glass bead

carried by Kinesins

12/57

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Transcription Factor in Yeast, GCN4, Leucine Zipper

Peptide basedPeptide based NanoNano--GripperGripper

Collaborator: Prof. Martin Yarmush, Center of Engineering in Medicine, MGH - Harvard

The tweezer mechanism should be reversible

Introduce amino acids with different degree of ionization at varying pH

Specifically histidines can be incorporated at eand g positions

Ionized amino acids will generate repulsive electrostatic charges andmake the helices move away

The hydrophobic interactions should bring the helices back once the pHis increased

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Peptide basedPeptide based NanoNano--Gripper:Gripper:Potential ApplicationsPotential ApplicationsMetal-ion Sensor

Schematic of a MolecularTweezer based bio-sensor for metallic ions.

The nanoTweezer bindsthe metallic ions atneutral pH and canrelease them at low pH.

Molecular Switch

Schematic of a MolecularTweezer based molecular switchor a pH sensor which relies onthe change in conformation atlow pH. (a) At pH 7 the peptide

is in compact configuration andthe ions have access to the goldsubstrate; (b) At low pH thepeptide is in open configurationand the access of the ions isblocked by the passivatingdodecanethiol layers resulting inreduced conductivity.

low pH

Dodecanethiollayers

thiotic acidlinker

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Peptide basedPeptide based NanoNano--Gripper:Gripper:

ArchitecturesArchitectures

Wild-type Mutant M1 Mutant M2 Mutant M3 Control M3CT

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Peptide basedPeptide based NanoNano--Gripper:Gripper:

ResultsResults

pH = 4.0

pH = 7.0

A

pH = 4.0

pH = 7.0

B

-20 0 20

pH = 4.0

pH = 7.0

C

Frequency (MHz)0 2 4 6

pH = 4.0

pH = 7.0

Distance (nm)

D

k =0.2 k =0.4k =0.2 k =0.4

Displacement Calculation Using MD Simulations

Force Calculations Using MD Simulations

Experimental Verification Using ESR Spectrocopy

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Viral Protein Nano Motor

Influenza hemagglutinin (HA) is aviral surface protein.

Upon interaction with a cell surfacereceptor, it is endocytosed.

In the endosome, the pH drops to5.0 and the HA protein undergoes a

dramatic conformational change topromote fusion.

The lower pH of 5.0 allows theprotein to cross an energy barrierand refold into a more stable

conformation. Computational and experimental

study showed the validity of theconcepts and its dependence ontemperature and salt concentration.

Collaborator: Prof. Martin Yarmush, Center of Engineering in Medicine, MGH - Harvard

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NanoActuators and NanoSensors for

Medical Applications - NANOMA

Early cancer stage I

Microcaprule-based drug delivey

Magnetic microcapsule sterring using

MRI ystem

1. Enhanced diagnostics usingMRI,

2. In-Vivo propulsion and

navigation,

3. Targeted drug del ivery using

functionalized nanovectors.

New approach for diagnosing and

treating breast cancer :

NANOMA aims at developing drug delivery microrobotic systems (composed of nanoActuators

and nanoSensors) for the propulsion and navigation of ferromagnetic microcapsules in the

cardiovascular system through the induction on magnetic gradients.

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Nanorobots for the Oil Industry

TRANSCEIVER ON BORE HOLE;

HARDWIRED TO THE DATA

CENTERNANOBOT

WIRELESS POWER &

DATA TRANSFER

DATA CENTER

OIL

RESERVOIR

BOREHOLE

Develop novel nanobots for the monitoring of deep oil reservoirs

Chemical Sensor

Pressure Sensor

Temperature Sensor

Power Source

Data Storage

Wireless

Communication

Magnetic Plates

Fish Tale Propulsion

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Future Challenges for Nanorobotics

Chemical Sensor

Pressure Sensor

Temperature Sensor

Power Source

Data Storage

Wireless

Communication

Magnetic Plates

Fish Tale Propulsion Assembly of a Fully FunctionalNanorobot

Closed Loop Control and Guidance atthe Nano-Scale

Wirelless Communication at the Nano-Scale Data Transfer

Power Generation at the Nanoscale

Accurate Modeling at the Nanoscale

Going Smaller and Smaller (~100nmtotal)

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Senior Investigator Team

Dr. M. Yarmush

Professor, Center ofEngineering in Medicine,MGH / Harvard Medical School

Dr. Yung-Joon Jung

Assistant Professor, Nanomanufacturing

Mechanical Engineering, Northeastern University

Dr. Antoine Ferreira

ProfessorModeling and ControlUniversity of Orleans, France

Dr. C. Mavroidis

Professor, RoboticsMechanical Engineering,Northeastern University

Dr. Marianna Bei

Assistant Professor

Molecular GeneticsMGH / Harvard Medical School

Dr. David Budil

Associate ProfessorChemistry and Chemical Biology

Northeastern University

Engineering Biomedical

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Acknowledgments

NASA Institute of Advanced Concepts(NIAC) Phase II Grant

NSF Nanomanufacturing Program NIRT Grant