Nanotechnology in Bionic Research

Dr. Simon Moulton QEII Fellow

ARC Centre of Excellence for Electromaterials Science (ACES) Intelligent Polymer Research Institute University of Wollongong 1

What Defines Nanotechnology? Any thing that has one dimension less than 100 nm

MACRO

1m

1 mm MICRO

NANO MOLECULAR

Synthetic

Natural

Civil Structures Manufactured Products

Animals

Raw Materials

Insects

1 m

Silicon Transistors

100 nm

Colloid Particles Single Molecules Atoms

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Nerves Cells

Bacteria Proteins

Human Hair!

Fantasy

and

www.uml.edu/.../media/nanotechnology-kd-001.jpg

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Fact

Pros and Cons • Entertainment – IPOD Nano

• Unknown technology (similar to GM foods – fear of the unknown)

• Medicine/Health – Cancer therapy – Sun screens

• Health – asbestos (CNTs) – Cell membranes (nanoparticles) 4

Bio Biology

nics Electronics LUIGI GALVANI’S ANIMAL ELECTRICITY

1791

2009

• Metals as Electrodes

• Organic Materials

Fibers

H N

H N N H

Platinum Electrodes

H N N H

A-

A-

PPy

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N H

x

Bionics? The University of Melbourne Bionic Ear 1978

The Bionic Man Col. Steve Austin 1973

GCLARK FOUNDATION/NLA

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Bionic Ear:

Bionic Eye

Cochlear Implant

The Argus II bionic eye is currently undergoing trials in 50-75 patients in the US. The system uses a spectacle mounted camera that feeds visual information to 60 electrodes implanted in the retina.

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Cochlear implants are one of the oldest pieces of the bionic man.

Bionics  Enhanced Performance Implantables  Wearables for Prosthetics and Monitoring

MAYBE THE BIONIC GAMES?

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BIONICS IN SPORT Oscar Pistorius - also known as ‘Blade Runner’ is a double leg amputee who is using specially developed artificial legs to compete in races. A world record holder in the 100, 200 and 400 meters Paralympic events, Pistorius was denied by the International Association of Athletics Federations (IAAF) his application to participate in the 2008 Summer Olympics. The IAAF argued that his prosthetic racing legs give him a clear competitive advantage. On May 16, the IAAF’s decision was overturned by the Court of Arbitration for Sport, allowing Pistorius to participate in the Olympics if he could make the minimum qualifying time.

Oscar Pitorius - the “blade runner”

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BIONICS FOR DEFENSE

U.S. Department of Defense Uses Futuristic Robotic Technology for a New Bionic Hand for Sgt. Juan Arredondo an Iraq War Veteran who Lost His Hand on Patrol.

http://blog.800hightech.com/bionic-hand-iraq-war-veteran/782/

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Not just Ordinary Electromaterials…. + A

oxidation n

A-

N H

Switching Surface Interactions

+ A- N

H

H N

N H

N H

n

Controlled Release of Active Molecules

H N A-

+ e-

+

- e-

Mechanical Level Switching

H N

H N

N H

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N H

+

2A-

Novel Materials – Novel Structures – Unforeseen Opportunities!!  Conducting Polymer (micro) Grid

 A Novel Fluid Transfer System

Videos courtesy of Shannon Little

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Nanostructured Electro Materials MACRO Human Hair MICRO NANO

1m

1 mm 1 m

100 nm

MOLECULAR

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Can we achieve temporal distribution of function?  External stimulation  Response to the biological environment  e.g. biodegradation  swelling (phase change)

 Galvanic coupling (Functional batteries)

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Control at the Nano Level

+ A- N

H

H N A-

H N

N H

+

e-e H

+ e-

H N

N

- e-

N H

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N H

+

2A-

ACES - BIONICS  Advanced Cochlear Electrodes (with an Eye on the Eye)

 Nerve Regeneration (Peripheral and Spinal Cord)

 Muscle Regeneration  Epilepsy Detection and Control  Bionic Stents (Boston Scientific)

Infection Control 16

Bionic Implants - Advanced Cochlear Implant Electrode Spiral Ganglion Neurite Explant Nerve cell body Nerve fibres

Electrode-Cellular Interface, G.G. Wallace, S.E. Moulton, G.M. Clark, Science 2009, 324, 185-186.

Safety studies commenced

Electrochemical data obtained

Carbon nanotube structures as implant electrodes 17

Nanobionics – Advanced cochlear implants

Middle Ear

Brain

Mastoid

Apical (Low frequency)

Cochlea (Inner Ear)

Organ of Corti Basal (High frequency)

Auditory Nerve

Fluid canals GCLARK FOUNDATION/NLA 18

Nanobionics – Advanced cochlear implants

Organ of Corti Outer hair cell

Inner hair cell

Basilar membrane

Peripheral auditory nerve fibres 19

Brain GCLARK FOUNDATION/NLA

Nanobionics – Advanced cochlear implants

Cochlea and Auditory Nerves

Electrode GCLARK FOUNDATION/NLA

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Brain

Introducing an Additional Growth Factor (BDNF) PPy/pTS/NT3

Electro-stimulated

Non-stimulated

PPy/pTS

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PPy/pTS/NT3/BDNF

Dual Neurotrophins: Synergy at Work BDNF

PPy/pTS/NT-3/BDNF Cochlear explant

NT-3

No Electrical stimulation

Electrical stimulation

NT-3/BDNF

Brain

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A Nanostructured Platform (Patent Pending) Ppy/pTS/NT-3

MWNT forest PEDOT SIBS

SIBS = poly(styrene-b-isobutylene-b-styrene) non-conducting, very stretchy polymer used in several tissue engineering applications recently FDA-approved as coronary stent coating PEDOT = Polyethylenedioxythiophene conducting polymer which has been used for several cell culturing application, but not widely explored as a biomaterial MWNT= multi-walled carbon nanotubes there is lots of controversy about the toxicity/biocompatibility of nanotubes, so the compatibility of tissues with this component is one matter that needs to be addressed

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Nanostructured PPys for Controlled Release PPy deposited on tips of CNTs

Comparison of CNT Array to Flat Film 24

Spinal Cord Regeneration Injured Spinal Cord

Repair of Lesion

Hydrogels and Fibres

Biodegradable Fibre Constructs

Conductive polymer materials for controlled release Wet fibre spinning to produce microdimensional structure 25

Schematic Representation of Wet-spinning Fibers

(a)

(a)

syringe and pump

PLGA:PLA fibers

coagulation baths linear controller

(b)

spool

(c)

Scale bars are 100 m

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Fibre Spinning

Ink Jet Printing

Vapour phase PPy/pTS on glass – oxidant printed with 10pL cartridge

75:25 PLA/PLGA fibers

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Nanofabricated Platforms

E Schwann cell migration front

DRG

PLA/PLGA fibres

C

PPy Mylar

G DRG

Axonal growth front PLA/PLGA fibres

Scale bar = 50 m

PPy Mylar

Scale bar = 500 m

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MUSCLE REGENERATION

 Muscular Diseases  Damage Due to Trauma  Grow / Replace Muscle Tissue 29

The Bio-Synthetic Cell Culture Platform

(a) 1. Wet-spun PLA:PLGA fibers on gold-coated mylar substrate

2. PPy polymerization of the exposed gold surface

Formation of the linear cell-seeded bio-synthetic fiber constructs. (a) The two-step (b) fabrication of the hybrid platform involves: (1) wetspinning of PLA:PLGA fibers onto a gold-coated mylar substrate to create an aligned micro-fiber array pattern, and (2) exclusive electrochemical modification of the(2 days) exposed gold 2.surface of the (4 days) 1. Myoblast proliferation Myotube differentiation substrate with the conducting polymer polypyrrole (PPy). (b) The compatibility of the hybrid platform towards skeletal muscle was assessed by: (1) allowing the cells to proliferate and adhere for 2 days, and (2) inducing their differentiation for 4 days.

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Fluorescence Images of Differentiated, Multinucleated Desmin (Green) Expressing Myotubes

(a)

(c)

(b) Fluorescence images of differentiated, multinucleated desmin (green) expressing myotubes on PPy/pTS substrate (a-b) with and (c-d) without the presence of PLA:PLGA fiber array. Cell nuclei are shown in blue. Scale bars are 200 m.

(d)

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Novel Ex Vivo Platform for Muscle Cell Growth

• Myotubes on fibres were most prominent on composites with narrow gaps between fibres. • Confirming prior results, myotubes tend to align along the fibre axis. • Presence of fibres also constricts the directionality of the myotubes on Ppy.

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Novel Ex Vivo Platform for Muscle Cell Growth B

C A

A

B

C

Ppy surface

Multinucleate myofibres were observed to align on the PLGA:PLA fibres, and some on PPy surface, forming linear cell-seeded “bio-synthetic” muscle fiber 33

The Implantable Conduit Spatial Distribution of Growth Factor Molecules in 3-D

Aligned Fiber Structure

In-built Power Supply

Distribution of Stem Cells

Biodegradable

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Epilepsy Detection and Control  Epilepsy is commonest serious neurological illness after stroke.

Current Treatments  About 1% of the population affected by recurrent seizures.

 Anti Convulsant Drugs  Electrical Stimulation

 5% will have seizures during their life.

Prof. Mark Cook, St Vincent’s Hospital and University of Melbourne. 35

Warning Some of the next slides contain medical images

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Detection

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Electrode Design

SEM courtesy of Dr Jun Chen

More electrodes = more data More electrode = connection issues 38

Targeted Drug Delivery •

•

•

Current therapeutic interventions for epilepsy, control seizures in only around 60% of affected individuals with the remaining people un-responsive to current therapeutic interventions. Side effects of systemic anti-convulsant medications administration include; – Nausea – Rashes – Weight changes – Dizziness Importantly, these side effects are a major factor limiting these drugs’ effectiveness in controlling epileptic seizures by preventing use of larger doses.

•

In addition, use of some of the stronger anti-convulsant drugs (eg Leviteracetam and phenytoin) is severely restricted due to the need for their systemic administration.

•

The local delivery of anti-convulsant drugs only to the brain regions involved in the epileptic seizure activity could prevent the severe side effects caused by systemic delivery.

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in vivo degradable polymer based drug delivery PLA-PLGA + Leviteracetam

3 mm 3 mm

Data and images courtesy of Dr Toni Campbell and Miss Amy Halliday.

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Other Materials • Wet-spinning – Incorporation of AEDs in fibres – AED loaded fibres woven into sheets – Vary pore size

• Microparticles (Spray Drying) • Nanoparticle (Electrospray)

•Layer-by-Layer

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Seizure Initiated Release Epilepsy Research 39 (2000) 103–114: An automated drug delivery system for focal epilepsy, Alan G. Stein et al

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Parameters for drug release V = ~130 mV

Voltage (mV)

Polypyrrole + neurtrophin-3 [2]

Polypyrrole + dexamethasone [1] Effect of Frequency

General trend is that more release is observed at slow frequencies.

Speed of Delivery

Require the drug to be released within the same time frame as seizure onset.

1 Galvanic coupling conducting polymers to biodegradable Mg initiates autonomously powered drug release. S.E Moulton, et al, J. Mater. Chem.18, 3608-13, 2008. 2 Optimizing the Incorporation and Release of a Neurotrophic Factor using Conducting Polypyrrole. B. C. Thompson, et al, Journal of Controlled Release, 116, 285-294 2006.

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• take multifunctional materials from fundamental research to proof of concept $52 million from the Federal Government A.I.I.M: PROCESSING AND DEVICES

EXISTING A.I.I.M BUILDING EXISTING IC CENTRAL

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Targeted End Users: Projects  Shorter Term  Medium Term  Longer Term

Collaborator Initiated Projects

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An invitation to engage ….  In current projects  In new collaborative ventures From Basic R&D to Processing and Prototype Development

Become a Foundation Partner …

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Major Equipment  Fitting out of workshop/engineering design area  Scale up of organic/materials synthesis (100 L capacity)  Fabrication equipment including:        

Ink-jet printing 3D printing Reel to reel printing Wet-spinning Electrospinning Dry spinning capabilities Knitting and weaving Excimer laser capabilities

 Bio fabrication facilities will be housed in PCl environment

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Direct-Print Scaffolds Produced by nscrytp

Thankyou

Acknowledgments ARC NHMRC ACES staff and students

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